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Review

Nucleic Acids as Biotools at the Interface between Chemistry and Nanomedicine in the COVID-19 Era

by
Nicola Borbone
1,
Ilaria Piccialli
2,
Andrea Patrizia Falanga
1,
Vincenzo Piccialli
3,
Giovanni N. Roviello
4,* and
Giorgia Oliviero
5
1
Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
2
Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy
3
Department of Chemical Sciences, University of Naples Federico II, Via Cintia 26, 80126 Naples, Italy
4
Institute of Biostructures and Bioimaging, Italian National Council for Research (IBB-CNR), Area di Ricerca Site and Headquarters, Via Pietro Castellino 111, 80131 Naples, Italy
5
Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(8), 4359; https://doi.org/10.3390/ijms23084359
Submission received: 7 March 2022 / Revised: 11 April 2022 / Accepted: 12 April 2022 / Published: 14 April 2022
(This article belongs to the Section Molecular Pharmacology)
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Versions Notes

Abstract

:
The recent development of mRNA vaccines against the SARS-CoV-2 infection has turned the spotlight on the potential of nucleic acids as innovative prophylactic agents and as diagnostic and therapeutic tools. Until now, their use has been severely limited by their reduced half-life in the biological environment and the difficulties related to their transport to target cells. These limiting aspects can now be overcome by resorting to chemical modifications in the drug and using appropriate nanocarriers, respectively. Oligonucleotides can interact with complementary sequences of nucleic acid targets, forming stable complexes and determining their loss of function. An alternative strategy uses nucleic acid aptamers that, like the antibodies, bind to specific proteins to modulate their activity. In this review, the authors will examine the recent literature on nucleic acids-based strategies in the COVID-19 era, focusing the attention on their applications for the prophylaxis of COVID-19, but also on antisense- and aptamer-based strategies directed to the diagnosis and therapy of the coronavirus pandemic.

1. Introduction

The COVID-19 (coronavirus disease 19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing enormous difficulties around the globe from both a sanitary and socioeconomic perspective [1,2,3,4,5,6,7,8,9,10]. Currently, the world is waiting for effective benefits following the mass vaccination campaign conducted in some parts of the globe using the developed anti-COVID-19 vaccines. However, despite the mass immunization campaign [11,12] and the efforts of pharmaceutical companies and the scientific community to devise effective therapies via new drug development [13,14], drug repurposing [15,16], herbal medicine [17,18,19,20,21] and other recently proposed approaches [22,23,24,25,26], SARS-CoV-2 and other human coronaviruses [27,28] remain a major global issue due to their mutations, leaving our future unclear. The recent development of DNA- and mRNA-carrying vaccines [29,30,31,32] able to elicit antibody production against the SARS-CoV-2 infection has recently recalled enormous attention to the potential uses of nucleic acids and their analogs as innovative biomedical tools. The oligonucleotide biotechnological use has been severely limited by their reduced half-life in the biological environment and the difficulties related to their delivery to target cells. Thus, some potent nucleic acid analogs (NAA) [33,34,35,36,37,38,39,40,41,42,43] are currently being utilized in anti-COVID-19 strategies because they allow one to overcome some of these limiting aspects by resorting to chemical modifications in the oligonucleotide and by using appropriate nanocarriers [44,45]. Like natural nucleic acids, NAAs can interact with complementary sequences of nucleic acid targets, forming stable complexes [46,47] and determining their loss of function [48]. For example, the binding of a peptide nucleic acid (PNA), locked nucleic acid (LNA), morpholino (PMO), or another synthetic analog [49] to the complementary nucleic acid target may determine (i) the inhibition of mRNA translation to the corresponding protein (antisense strategy), (ii) the blocking of gene transcription via specific binding with gene promoters (antigene strategy), and (iii) numerous biomolecular events exploited in several diagnostic applications [49]. An alternative strategy uses nucleic acids aptamers that, like the antibodies, bind to specific proteins to modulate their activity [50,51,52,53,54,55,56,57,58]. In this regard, i-motif [59,60] and G-quadruplex forming oligonucleotides [61,62,63] are particularly relevant as their specific role as aptamers was explored in vitro and, in some cases, find applications in biomedical strategies [64,65,66,67,68,69]. Drug discovery campaigns against COVID-19 are targeting not only viral proteins (such as Mpro main protease [70,71]) but also the viral RNA genome [72], with particular attention paid to highly conserved and expression-relevant tracts [73] (Figure 1).
This review will examine the recent literature on nucleic acid-based technologies in the COVID-19 era. We will focus on the main prophylactic, therapeutic and diagnostic DNA- and RNA-based tools currently under examination or in use in the fight against SARS-CoV-2.

2. DNA and RNA-Containing Vaccines in the Fight against COVID-19

Antiviral vaccines can generally be classified into three categories: (live-attenuated or inactivated) virus-based, protein-based, and nucleic acid-based [74]. The first two approaches have been the conventional methods that rely on unharmful forms of the virus or proteins directly delivered as immunogens to induce the immune response in the host. On the other hand, nucleic acid-based vaccines are delivered via nucleic acid vectors to host cells, where DNA or RNA genes will be expressed in the host to produce corresponding antigens that activate the adaptive and humoral immune response [74]. All three strategies have been explored for COVID-19, but currently (as of 4 February 2022), only gene vaccines are available in Western countries, even though the protein-based NVX-CoV2373 vaccine developed by the American Novavax should become available soon [75,76], and the inactivated whole virus vaccine VLA2001 from the French Valneva could be approved in the upcoming months [76]. One of the advantages of nucleic-acid-based vaccines is the easiness and relatively high rapidity of their manufacturing [74]. They can immediately be synthesized when the immunogen sequence is made available, and the process can be easily scalable. With respect to DNA-based vaccines, an mRNA vaccine expresses the antigen protein directly via translation from the mRNA after its transfection [74]. These vaccines are believed to possess higher biosafety than DNA-based vaccines because the mRNA is less likely integrated into the genome than a DNA-based vaccine, as the translation of the antigens in the case of mRNA vaccines takes place in the cytoplasm and not in the nucleus, where the DNA vaccines start to work [77]. However, several studies suggest that the risk of genomic integration, even if diminished compared to DNA vaccines, also remains for those based on mRNA, considering that eukaryotic cells may exert, to some extent, a reverse transcription activity [78,79,80] that could produce DNA theoretically starting from the vaccine-delivered mRNAs [81,82]. An advantage of nucleic acid-based vaccines over protein-based vaccines is that they may lead to antigens better mimicking the viral protein structure, including the post-translational modifications. In fact, while protein-based vaccines are often produced from bacteria, mRNA vaccines are translated by the host translation machinery. Nonetheless, the novel NVX-CoV2373 vaccine was developed using insect cells that can perform most of the desired post-translational modifications. As for the storage and transportation, DNA and mRNA vaccines must be stored and transported at low or ultra-low temperatures [83], whereas inactivated virus- and protein-based vaccines [84] require less stringent conditions. However, innovative lipid nanoparticle technologies are significantly improving the stability characteristics of mRNA vaccines that may require less stringent conditions [83].
From a molecular perspective, one of the most reliable strategies to fight SARS-CoV-2 consists of the administration of the nucleic information (DNA or RNA) that the host cellular machinery uses for the production of SARS-CoV-2 spike (S) protein, which has been generally used as the antigen of DNA vaccines used against COVID-19 (Table 1). Once produced in human cells, S protein may provoke the immune system to respond with cellular and humoral defenses, retaining the information in memory immune cells. In this way, the organism is prepared to counteract virus infection in the case of subsequent exposure to SARS-CoV-2. Generally, these prophylactic agents are administered in a two-dose immunization scheme, with both injections being administered intramuscularly, often within a three-week interval. Interestingly, the nucleic acid-based vaccination is currently the most exploited anti-COVID-19 prophylaxis in the Western world, and here below, we will give some details on the currently most in-vogue vaccines belonging to this category of vaccines.

2.1. DNA-Carrying COVID-19 Vaccines

They are often classified as “virally vectored vaccines” or “adenovirus vector vaccines” being based on vaccine vectors, but they should be more correctly denominated as adenovirus vector-based DNA vaccines to underline the nature of their cargo [76]. The most widely utilized in Western countries, i.e., the ChAdOx1-S/AZD1222-Spike [85] vaccine developed by the University of Oxford in collaboration with AstraZeneca (Cambridge, UK) pharmaceutical company (Table 1), used a Chimpanzee non-replicating viral vector that contains synthetic DNA encoding the S protein of SARS-CoV-2. Thus, the ChAdOx1-S/AZD1222 expresses the S protein gene, which instructs the human cells to produce the protein, allowing the body to generate an effective immune response. Clinical trials showed efficacy in participants who received two doses of the vaccine irrespective of the interval between the doses of about 63.1%, based on a median follow-up of 80 days or higher when this interval was longer [86]. The vaccine was manufactured by SK Bioscience Co., Ltd. (Pangyo-ro, Korea), under the name ChAdOx1-S, and the Serum Institute of India (Pune, India) named COVISHIELD [87]. Even though it is less common than the ChAdOx1-S/AZD1222, the Ad26.CoV2.S vaccine developed by Janssen Pharmaceuticals Johnson & Johnson (Beerse, Belgium) is worth mentioning. Ad26.CoV2.S is a non-replicating viral vector vaccine consisting of a human adenovirus vector, with a DNA genome, into which has been inserted the gene that encodes the S protein of SARS-CoV-2. The efficacy was 66.0% in phase-3 clinical trials (Table 1) [88].

2.2. RNA-Carrying COVID-19 Vaccines (mRNA Vaccines)

The most currently used vaccine type in Europe and North America, these vaccines exploit mRNAs to instruct human cells to produce the S protein [74]. Since mRNA vaccines do not need to reach the cell nucleus like the DNA-based ones, they are of higher practical significance. Although RNA is known to be a relatively unstable nucleic acid, novel vaccine nanotechnologies were developed to improve both mRNA stability and S protein translation efficiency, with consequent enhanced immune responses by the host cell. More in detail, lipid-nanoparticle encapsulation [89,90,91,92] of the vaccine is a strategy often used to optimize the delivery of the mRNAs for intradermal or intramuscular administration [93]. The leading exponents of this family of anti-COVID-19 prophylactic agents are BNT162/Comirnaty and mRNA-1273 (Table 1) [94]. The former is a lipid-nanoparticle encapsulated mRNA-based vaccine developed by BioNTech (Mainz, Germany) and Pfizer (New York, NY, USA), partnered with Fosun Pharma (Shangai, China), which encodes the RBD (receptor-binding domain) domain of the SARS-CoV-2 S protein. BNT162, loaded into a patented lipid-nanoparticle composed of ionizable amino lipid, phospholipid, cholesterol, and a PEGylated lipid (at a ratio of 50:10:38.5:1.5 mol/mol, Figure 2) [95], uses a modified 4284 nucleotides long mRNA [96] and includes the T4 fibrin-derived trimerization domain, which serves to enhance the immune response [88]. On the other hand, mRNA-1273, developed by Moderna (Cambridge, MA, USA) in collaboration with the American National Institute of Allergy and Infectious Diseases (NIAID, Bethesda, MD, USA), is a vaccine based on a 4004 nucleotides long mRNA [97] expressing the full-length prefusion stabilized S protein of SARS-CoV-2. In mRNA-1273, the mRNA strand is encapsulated by two proprietary cationic lipidic nanoparticles (WO2017070626 and WO2018115527) whose composition was described as SM-102, polyethylene glycol-2000-dimyristoyl glycerol (PEG2000-DMG), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, Figure 2) [95].
As for dosages/schedule, routes of administration, and efficacies, two intramuscular doses are needed for both mRNA vaccines, 21 days apart (30 μg per dose) for BNT162/Comirnaty and 28 days apart (100 μg per dose) in the case of mRNA-1273. The confirmed efficacy of the BNT162/Comirnaty vaccine is 95.0% (measured starting from seven days after the second dose), while that of mRNA-1273 is 94.1% (measured starting from two weeks after the second dose) (Table 1) [98].

2.3. Chemical and Nanotechnological Optimization of mRNA Vaccine Design

Though exempt from any risks of genomic integration [77], the typical vaccine development using viruses or protein-based systems involves time-consuming steps that appear impractical for responding rapidly to any pandemic caused by newly emerging pathogens. As explained above, nucleic acid-based vaccines possess distinctive advantages of rapid development and versatility that led to the development of multiple COVID-19 DNA and mRNA vaccines. Among these, mRNA vaccines seem to have higher protective efficacy than DNA vaccines, but special strategies are needed to guarantee their safety, stability, and consequent efficacy due to some intrinsic RNA molecular features. In fact, RNA is particularly prone to enzymatic degradation by the RNases present in the plasma and serum. Moreover, RNA molecules in mRNA vaccines, being exogenous molecules, are seen by the human cellular machinery as an immunological mimic of viral infection, which provokes an immediate immune response by host cells. Hence, the importance of nanotechnologies aimed at maximizing the stability of RNA in mRNA vaccines and limiting the innate immune response in the host [99,100].
Endogenously, mRNAs undergo post-transcriptional modifications, such as 5′-capping [101] and polyadenylation [102,103], needed for mRNA stabilization (protecting mRNA from exonuclease activity) and efficient translation (facilitating pre-mRNA splicing and serving as the binding site for the translation initiation complex). 5′-capping includes the addition of 7-methylguanosine (m7G) at the 5′ end of the first ribonucleotide of mRNA molecules via a 5′ to 5′ linkage and the methylation of the 2′-OH of the ribose moiety of the same ribonucleotide to form m7GpppNm (Figure 3a). Interestingly, the host can discriminate between the self versus the exogenous mRNA thanks to the presence of the 5′-cap. The last observation explains why adding an m7GpppNm cap to the 5′-end of mRNA vaccines’ RNA strand is a highly desirable mRNA modification [101]. The polyadenylation (i.e., the addition of a poly rA tail at the 3′-OH of pre-mRNA) is another factor that stabilizes mRNA and promotes protein translation [102,103], as the length of the poly(A) tail is closely associated with the translation efficiency. However, the information on the nature of the poly(A) signal sequence was reported only in the case of the BNT162/Comirnaty vaccine [poly rA tail: A30(GCATATGACT)A70], whereas it remains proprietary and undisclosed for the Moderna’s counterpart [96].
Nucleoside modifications and, especially, the incorporation of pseudouridine (Figure 3b) into mRNA molecules may suppress the immune response by evading the activation of TLR-3, -7, and -8. Consequently, in the BNT162/Comirnaty vaccine, uridine residues were replaced by 1-methyl pseudouridine modification to reduce the innate immune response and enhance the stability of the exogenous mRNA [104].
Many liposome-based transfection reagents based on cationic lipids have been formulated to improve the transfection efficiency of mRNAs, which is generally low in the case of naked oligoribonucleotides [105]. Generally, the lipid components of mRNA vaccines are proprietary and include different cationic polypeptides, positively charged lipids, polymers, dendrimers, or micelles [106]. Lipid nanoparticles encapsulate their mRNA cargo into the stable lipid bilayer, which is internalized by recipient cells via endocytosis. More in detail, after the injection, the mRNA-lipid nanoparticle complexes enter muscle cells via endocytosis pathways, and then the translation of the mRNA leads to translates forming a metastable trimeric prefusion spike protein. Blood vessels adjacent to the muscles are then believed to recruit infiltrating antigen-presenting cells [107].

2.4. Nanotechnologies in the Development of Potential COVID-19 Vaccines

Coronaviruses are nanoscale biostructures against which nanotechnology can be exploited to realize vaccines and immune engineering applications [108]. Live attenuated and inactivated vaccines, viral vectors, and mRNA-lipid nanoparticles [109,110] (Figure 4a) constitute examples of nano-biotechnological products so efficient against SARS-CoV-2. The use of nanomaterials as carriers of antigens or prophylactic mRNAs and DNAs is a recent biotechnological approach that proved successful in COVID-19 vaccine design technology. In a nanotechnological vaccine, antigens and nanoparticles mutually interact by adsorption, entrapment, and conjugation. As for the materials constituting the nanoparticles, liposomes, nanopolymers, quantum dots, and inorganic nanoparticles are conventional vehicles for subunit vaccines and nucleic acids [111]. Several types of lipids are also used, including cholesterol and ionizable lipids, which, being cationic, interact with the negatively charged RNAs.
Moreover, the conjugation of lipids to polyethylene glycol chains (Figure 4a, green) proved effective in shielding the mRNA cargo from the host immune system, thus prolonging a vaccine’s lifetime following intramuscular injection. Protein nanoparticles were also proposed in the realization of vaccines against SARS-CoV-2 (Figure 4b) [112]. The vaccine strategy, in this case, was based on the display of the S protein receptor-binding domain (RBD) on a synthetic virus-like particle platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology [112].

3. DNA and RNA Targeting in the COVID-19 Era

3.1. RNA Targeting in the Diagnostics of COVID-19

Rapid screening of infected individuals from a large population is important in epidemiology, especially in controlling the spread of COVID-19 infections [114]. The reverse transcription polymerase chain reaction (RT-PCR) assay is the diagnostic standard for COVID-19. In contrast, rapid antigen tests based on lateral immunochromatography and using different matrices, including direct culture supernatants and dry swabs [115], could be used as point-of-care detection of SARS-CoV-2 antigens with several advantages over the RT-PCR assays including shorter turn-around times and lower costs [114]. However, their sensitivity in detecting the SARS-CoV-2 virus remains lower than RT-PCR (0.68 compared to RT-PCR), especially in low viral loads. Even though RT-PCR tests remain the gold standard for population-wide screening of COVID-19 and other epidemics, significant limitations prevent the large scale application of this technology, which include the significantly higher costs and longer turnaround times due to time-consuming nucleic acid extraction and amplification steps, and the required equipment for testing [114]. An RNA targeting strategy was thus ideated based on a direct nucleic acid assay that used a graphene field-effect transistor (g-FET) and Y-shaped DNA dual probes [116]. The method relied on Y-dual probes modified on g-FET simultaneously targeting nucleocapsid (N) and viral replicate polyprotein open reading frame (ORF1ab) genes of the SARS-CoV-2 RNA genome. Interestingly, the assay was associated with a high recognition ratio and a limit of detection one-two order of magnitude lower than other nucleic acid assays (0.03 copy μL−1). Another advantage of this RNA-targeting DNA-based assay was the rapidity of the nucleic acid testing (~1 min) compared to the longer times (up to 4 h) required by the other nucleic acid tests, along with the ultrasensitivity, easiness in operating features as well as capability in pooled testing [116].

3.2. COVID-19 Antisense Strategies

The outbreak of SARS in 2003 (caused by SARS-CoV-1) and the COVID-19 pandemic sixteen years later showed the world our vulnerability to coronavirus infections [117]. Given that periodic outbreaks of similar pandemics could occur in the future, the scientific community and pharmaceutical companies should be prepared to fast-track the production of vaccines and antiviral oligonucleotides acting as RNA-targeting therapeutics in antisense strategies directed against coronaviruses. More specifically, oligonucleotides and NAAs can target the SARS-CoV-2 RNA genome and regulatory RNA sequences, disrupt RNA secondary structures or host protein/virus RNA complexes, and provoke steric blocks (Table 2). The first antisense oligonucleotides reported against SARS-CoV-1, whose genome is closely related to SARS-CoV-2, targeted the ORF1a gene and the transcription regulatory RNA sequence located in the 5′-UTR region of the positive-sense RNA genome of SARS-CoV-2 [118]. These antisense oligonucleotides (antisense morpholino oligomers and peptide-conjugated antisense morpholino oligomers [P-PMOs], Figure 5) were endowed with high antiviral activity in vitro, revealing the potential capacity of the antisense nucleic acid analogs (NAA) for antiviral treatment against SARS-CoV-1 and, potentially, SARS-CoV-2. This work acted as a proof of concept for the efficiency of RNA-targeting NAAs as an antiviral treatment in the context of human coronavirus infections [118].
Notably, the SARS-CoV-2 genome can be targeted at any step of its life cycle by antisense oligonucleotides that allow for targeting any of the conserved sequences of both positive and negative RNA. Regarding the structure of the SARS-CoV-2 genome, whose knowledge is necessary for developing specific antisense oligonucleotides, it consists of a single-stranded RNA of ca. 30,000 nucleotides capped at the 5′ end and endowed with a 3′ poly rA-tail, as well as two short UTR-sequences [118]. SARS-CoV-2 RNA genome encodes 14 ORFs, of which ORF1a and ORF1b, at the 5′ end, encode the replicase polyprotein comprising ~2/3 of the entire genome. In addition to these nonstructural proteins, the remaining genome contains nine small ORFs encoding structural proteins such as nucleocapsid (N), envelope (E), spike (S), membrane (M), and others with accessory roles. SARS-CoV-2 RNAs include both subgenomic and genomic entities, with the first RNA tracts being translated into structural proteins and others with accessory roles.
On the other hand, genomic RNA is involved in replicating viral RNA before its incorporation into virions. In principle, any sequence of SARS-CoV-2 RNA genome is a potential target of antisense oligonucleotides, but genomic RNAs and replication steps are especially recommended for antisense strategies as targeting subgenomic entities is associated with lower antiviral efficacies [118]. After infection, SARS-CoV-2 replicates its genome inside the human cell using enzymes for replication encoded by the coronavirus itself. More in detail, the 5′ cap, and 3′ poly rA tail modifications allow direct translation of the nonstructural proteins encoded by genes ORF1a and ORF1b. Afterward, the assembly of the replicase-transcriptase complex (RTC) occurs, leading to the replication of the RNA genome alongside the discontinuous subgenomic mRNA transcription, mediated by short AU-rich transcription regulatory sequences, whose resulting subgenomic RNAs are further translated into the structural proteins and the others with various accessory roles. Huston et al. [119] applied a novel long amplicon strategy to resolve the secondary RNA structure of the coronavirus genome in infected cells, which revealed an elaborate SARS-CoV-2 genome architecture that included well-folded RNA regions, some of which were unique while others were conserved across beta-coronaviruses. They developed antisense oligonucleotides containing LNA (Figure 5) moieties as steric blockers and tested them in targeting two putative RNA regions within the SARS-CoV-2 genome [119]. The two oligonucleotides contained three consecutive LNAs at their 5′ and 3′ termini, whereas unmodified consecutive nucleotides within the strands were limited to three to prevent RNase-dependent activation. These NAA-based antisense strategies significantly inhibited the growth of SARS-CoV-2, demonstrating that the two targeted secondary RNA structures are critical for the life cycle of the coronavirus and that these LNA-containing antisense oligonucleotides disclose potential as anti-COVID-19 therapeutics [119].
Further investigations used antisense oligonucleotides carrying 2′-O-methoxyethyl (2′-MOE, Figure 5) and phosphorothioate (PS, Figure 5) backbone modifications as steric blockers to disrupt interactions between the host RNA binding proteins and SARS-CoV-2 RNA thanks to their enhanced steric blocking activity [121]. Moreover, RNase H-dependent antisense oligonucleotides, carrying LNA tracts at both ends, were used to target the SARS-CoV-2 stem-loop 2 motif (s2m) in the 3′-UTR of the cytosolic positive-sense RNA strand [120]. In addition to the terminal LNA tracts, the antisense oligonucleotides carried long stretches of unlocked ribonucleotides that ensured RNase H recruitment and, therefore, viral RNA cleavage. Interestingly, as RNase H is responsible for the cleavage of the targeted RNA in the duplexes formed by RNA and the antisense oligonucleotide, this latter remains intact and free to bind to other RNAs, while the SARS-CoV-2 RNA is cleaved in a sequence-specific manner, which led to inhibition of the replication of SARS-CoV-2 in infected cells [120]. Overall, these anti-COVID-19 RNA-targeting strategies seem to be promising, especially in view of targeting conserved RNA tracts in different variants of SARS-CoV-2 and other human coronaviruses. However, these approaches still need further research supporting their translation into clinics.

3.3. Aptamers and G-Quadruplex Structures for the Detection of SARS-CoV-2

While most anti-COVID-19 strategies were designed to target essential proteins within the SARS-CoV-2 genome, targeting RNA structural elements is also of crucial importance especially using the class of oligonucleotide aptamers [122]. This family is composed of oligonucleotides of different nature that, similarly to antibodies, recognize specific three-dimensional structures acting as “chemical antibodies” [123]. Thanks to oligonucleotide aptamers’ high affinity and specificity for their targets, they offer unique chemical and biological characteristics rendering them particularly suitable for novel biomedical applications, including in vitro diagnosis, biomarkers discovery, in vivo imaging, and therapy [123]. The highly conserved RNA structure within the s2m motif of SARS-CoV-2 was targeted by high-affinity L-DNA aptamers [124] to evaluate their therapeutic and diagnostic potential. Optimized L-DNA aptamers were found to bind selectively to s2m with affinities in the nanomolar range and proved capable of discriminating between the monomeric s2m stem-loop and the homodimer duplex. The L-DNA mode of recognition is highly structure-specific, allowing to differentiate s2m RNAs from different but closely related human coronaviruses, such as SARS-CoV-1 and SARS-CoV-2, differing by only two ribonucleotides. In addition, L-DNA aptamers induce significant conformational changes in s2m RNA structure upon their molecular recognition, with a potential role in disrupting or preventing protein–s2m binding [124].
G-quadruplex (G4) DNA or RNA is a non-canonical secondary structure resulting from assembling one, two, or four guanine-rich nucleic acids strands into a quadruple helix structure stabilized by coordination with suitable monovalent cations [125]. G4 structure and function are determined by factors such as the number and polarity of nucleotide strands, the type of metal ions, as well as the structural properties of their binding targets [125]. Targeting of the G4-folded SARS-CoV-2 RNA genome by specific aptamers appears to be a promising alternative method for SARS-CoV-2 detection [126]. In addition to their importance as aptamer targets, G4-forming oligonucleotides can also be used to realize G4 aptamer-based biosensors to detect SARS-CoV-2 surface proteins. Indeed, G4-based biosensors represent a valuable alternative to antibody-based detection of SARS-CoV-2 and other pathogens [126].
The use of aptamers for targeting SARS-CoV-2 RNA genomic tracts in COVID-19 therapy and diagnostic approaches based on the recognition of virus proteins are promising strategies thanks to the intrinsic specificity guaranteed by the aptamer technology. Nevertheless, the utility of these approaches is still to be evaluated in prospective clinical and diagnostic studies.

4. Conclusions

The outbreak of the COVID-19 pandemic showed our vulnerability to coronavirus infections, and given that other pandemics could attack humanity after the current crisis, the scientific community, together with pharmaceutical companies, should be prepared to fast-track the production not only of vaccines, but also of nucleic acid-based antisense tools and aptamers acting as RNA-targeting therapeutics against coronaviruses. Overall, the herein summarized applications of nucleic acids, and especially RNAs and NAAs, in the context of the fight against SARS-CoV-2 demonstrate the feasibility of using nucleic acids for mass immunization when the urgency of counteracting the virus spread does not allow waiting for the development of long-established live attenuated and inactivated virus- and protein-based vaccines. Additionally, the above literature reports show the importance of targeting SARS-CoV-2 RNA using antisense oligonucleotides and aptamers, which has important implications in diagnosing and treating the infectious disease caused by SARS-CoV-2. Remarkably, the high affinity and selectivity of oligonucleotide antisense devices and aptamers, coupled with the intrinsic nuclease resistance of NAA that can be easily introduced in their structures, enable novel opportunities for generating new tools and probes for interrogating RNA function in SARS-CoV-2 and related coronaviruses.

Author Contributions

All authors contributed to the conceptualization, literature collection, writing, editing, and reviewing of the article. All authors have read and agreed to the published version of the manuscript.

Funding

The APC was funded by Ministero dell’Università e della Ricerca FOE 2017 - ISBE-IT Joint Research Unit.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Antonietta Gargiulo (IBB CNR) for her help in the literature search. We thank D.S. Goodsell, the Illustration in Figure 4a was realized by D.S. Goodsell, RCSB Protein Data Bank (https://pdb101.rcsb.org/sci-art/goodsell-gallery/sars-cov-2-mrna-vaccine accessed on 4 February 2022).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Choi, H.; Chatterjee, P.; Hwang, M.; Lichtfouse, E.; Sharma, V.K.; Jinadatha, C. The viral phoenix: Enhanced infectivity and immunity evasion of SARS-CoV-2 variants. Environ. Chem. Lett. 2021, in press. [Google Scholar] [CrossRef]
  2. He, S.; Han, J.; Lichtfouse, E. Backward transmission of COVID-19 from humans to animals may propagate reinfections and induce vaccine failure. Environ. Chem. Lett. 2021, 19, 763–768. [Google Scholar] [CrossRef] [PubMed]
  3. Choi, H.; Chatterjee, P.; Lichtfouse, E.; Martel, J.A.; Hwang, M.; Jinadatha, C.; Sharma, V.K. Classical and alternative disinfection strategies to control the COVID-19 virus in healthcare facilities: A review. Environ. Chem. Lett. 2021, 19, 1945–1951. [Google Scholar] [CrossRef] [PubMed]
  4. Kumawat, M.; Umapathi, A.; Lichtfouse, E.; Daima, H.K. Nanozymes to fight the COVID-19 and future pandemics. Environ. Chem. Lett. 2021, 19, 3951–3957. [Google Scholar] [CrossRef] [PubMed]
  5. Dai, H.; Han, J.; Lichtfouse, E. Who is running faster, the virus or the vaccine? Environ. Chem. Lett. 2020, 18, 1761–1766. [Google Scholar] [CrossRef]
  6. Ufnalska, S.; Lichtfouse, E. Unanswered issues related to the COVID-19 pandemic. Environ. Chem. Lett. 2021, 19, 3523–3524. [Google Scholar] [CrossRef]
  7. Kim, D.; Lee, J.-Y.; Yang, J.-S.; Kim, J.W.; Kim, V.N.; Chang, H. The architecture of SARS-CoV-2 transcriptome. Cell 2020, 181, 914–921. [Google Scholar] [CrossRef]
  8. Wu, D.; Wu, T.; Liu, Q.; Yang, Z. The SARS-CoV-2 outbreak: What we know. Int. J. Infect. Dis. 2020, 94, 44–48. [Google Scholar] [CrossRef]
  9. Caterino, M.; Gelzo, M.; Sol, S.; Fedele, R.; Annunziata, A.; Calabrese, C.; Fiorentino, G.; D’Abbraccio, M.; Dell’Isola, C.; Fusco, F.M. Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19. Sci. Rep. 2021, 11, 2941. [Google Scholar] [CrossRef]
  10. Caterino, M.; Costanzo, M.; Fedele, R.; Cevenini, A.; Gelzo, M.; Di Minno, A.; Andolfo, I.; Capasso, M.; Russo, R.; Annunziata, A. The serum metabolome of moderate and severe COVID-19 patients reflects possible liver alterations involving carbon and nitrogen metabolism. Int. J. Mol. Sci. 2021, 22, 9548. [Google Scholar] [CrossRef]
  11. Castells, M.C.; Phillips, E.J. Maintaining safety with SARS-CoV-2 vaccines. N. Engl. J. Med. 2021, 384, 643–649. [Google Scholar] [CrossRef]
  12. Costanzo, M.; De Giglio, M.A.; Roviello, G.N. Anti-Coronavirus Vaccines: Past Investigations on SARS-CoV-1 and MERS-CoV, the Approved Vaccines from BioNTech/Pfizer, Moderna, Oxford/AstraZeneca and others under Development Against SARSCoV-2 Infection. Curr. Med. Chem. 2022, 29, 4–18. [Google Scholar] [CrossRef] [PubMed]
  13. Mahase, E. Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ 2021, 375, n2713. [Google Scholar] [CrossRef] [PubMed]
  14. Burki, T.K. The role of antiviral treatment in the COVID-19 pandemic. Lancet Resp. Med. 2022, 10, e18. [Google Scholar] [CrossRef]
  15. Borbone, N.; Piccialli, G.; Roviello, G.N.; Oliviero, G. Nucleoside analogs and nucleoside precursors as drugs in the fight against SARS-CoV-2 and other coronaviruses. Molecules 2021, 26, 986. [Google Scholar] [CrossRef] [PubMed]
  16. Singh, T.U.; Parida, S.; Lingaraju, M.C.; Kesavan, M.; Kumar, D.; Singh, R.K. Drug repurposing approach to fight COVID-19. Pharmacol. Rep. 2020, 72, 1479–1508. [Google Scholar] [CrossRef] [PubMed]
  17. Vicidomini, C.; Roviello, V.; Roviello, G.N. Molecular basis of the therapeutical potential of clove (Syzygium aromaticum L.) and clues to its anti-COVID-19 utility. Molecules 2021, 26, 1880. [Google Scholar] [CrossRef] [PubMed]
  18. Vicidomini, C.; Roviello, V.; Roviello, G.N. In silico investigation on the interaction of chiral phytochemicals from opuntia ficus-indica with SARS-CoV-2 Mpro. Symmetry 2021, 13, 1041. [Google Scholar] [CrossRef]
  19. Roviello, V.; Roviello, G.N. Lower COVID-19 mortality in Italian forested areas suggests immunoprotection by Mediterranean plants. Environ. Chem. Lett. 2021, 19, 699–710. [Google Scholar] [CrossRef]
  20. Ang, L.; Lee, H.W.; Kim, A.; Lee, J.A.; Zhang, J.; Lee, M.S. Herbal medicine for treatment of children diagnosed with COVID-19: A review of guidelines. Complement. Ther. Clin. 2020, 39, 101174. [Google Scholar] [CrossRef]
  21. Nugraha, R.V.; Ridwansyah, H.; Ghozali, M.; Khairani, A.F.; Atik, N. Traditional herbal medicine candidates as complementary treatments for COVID-19: A review of their mechanisms, pros and cons. Evid.-Based Complement. Altern. Med. 2020, 2020, 2560645. [Google Scholar] [CrossRef] [PubMed]
  22. Roviello, V.; Gilhen-Baker, M.; Vicidomini, C.; Roviello, G.N. Forest-bathing and physical activity as weapons against COVID-19: A review. Environ. Chem. Lett. 2022, 20, 131–140. [Google Scholar] [CrossRef] [PubMed]
  23. Roviello, V.; Roviello, G.N. Less COVID-19 deaths in southern and insular Italy explained by forest bathing, Mediterranean environment, and antiviral plant volatile organic compounds. Environ. Chem. Lett. 2022, 20, 7–17. [Google Scholar] [CrossRef] [PubMed]
  24. Roviello, V.; Scognamiglio, P.L.; Caruso, U.; Vicidomini, C.; Roviello, G.N. Evaluating In Silico the Potential Health and Environmental Benefits of Houseplant Volatile Organic Compounds for an Emerging ‘Indoor Forest Bathing’ Approach. Int. J. Environ. Res. Public Health 2022, 19, 273. [Google Scholar] [CrossRef]
  25. Roviello, V.; Gilhen-Baker, M.; Roviello, G.N.; Lichtfouse, E. River therapy. Environ. Chem. Lett. 2022; in press. [Google Scholar] [CrossRef]
  26. Gilhen-Baker, M.; Roviello, V.; Beresford-Kroeger, D.; Roviello, G.N. Old growth forests and large old trees as critical organisms connecting ecosystems and human health. A review. Environ. Chem. Lett. 2022, 20, 1529–1538. [Google Scholar] [CrossRef]
  27. Callaway, E.; Ledford, H. How to redesign COVID vaccines so they protect against variants. Nature 2021, 590, 15–16. [Google Scholar] [CrossRef]
  28. Koyama, T.; Weeraratne, D.; Snowdon, J.L.; Parida, L. Emergence of drift variants that may affect COVID-19 vaccine development and antibody treatment. Pathogens 2020, 9, 324. [Google Scholar] [CrossRef]
  29. Doerfler, W. Adenoviral Vector DNA-and SARS-CoV-2 mRNA-Based Covid-19 Vaccines: Possible Integration into the Human Genome-Are Adenoviral Genes Expressed in Vector-based Vaccines? Virus Res. 2021, 302, 198466. [Google Scholar] [CrossRef]
  30. Forni, G.; Mantovani, A. COVID-19 vaccines: Where we stand and challenges ahead. Cell Death Differ. 2021, 28, 626–639. [Google Scholar] [CrossRef]
  31. Shiravi, A.A.; Ardekani, A.; Sheikhbahaei, E.; Heshmat-Ghahdarijani, K. Cardiovascular Complications of SARS-CoV-2 Vaccines: An Overview. Cardiol. Ther. 2021, 11, 13–21. [Google Scholar] [CrossRef] [PubMed]
  32. De Soto, J.A.; DSSc, F. Evaluation of the Moderna, Pfizer/BioNtech, Astrazeneca/Oxford and Sputnik V Vaccines for COVID-19. ARJMCS 2021, 7, 408–414. [Google Scholar] [CrossRef]
  33. Karkare, S.; Bhatnagar, D. Promising nucleic acid analogs and mimics: Characteristic features and applications of PNA, LNA, and morpholino. Appl. Microbiol. Biot. 2006, 71, 575–586. [Google Scholar] [CrossRef] [PubMed]
  34. Roviello, V.; Musumeci, D.; Mokhir, A.; Roviello, G.N. Evidence of protein binding by a nucleopeptide based on a thyminedecorated L-diaminopropanoic acid through CD and in silico studies. Curr. Med. Chem. 2021, 28, 5004–5015. [Google Scholar] [CrossRef] [PubMed]
  35. Musumeci, D.; Mokhir, A.; Roviello, G.N. Synthesis and nucleic acid binding evaluation of a thyminyl L-diaminobutanoic acid-based nucleopeptide. Bioorg. Chem. 2020, 100, 103862. [Google Scholar] [CrossRef] [PubMed]
  36. Roviello, G.; Vicidomini, C.; Di Gaetano, S.; Capasso, D.; Musumeci, D.; Roviello, V. Solid phase synthesis and RNA-binding activity of an arginine-containing nucleopeptide. RSC Adv. 2016, 6, 14140–14148. [Google Scholar] [CrossRef] [Green Version]
  37. Musumeci, D.; Ullah, S.; Ikram, A.; Roviello, G.N. Novel insights on nucleopeptide binding: A spectroscopic and In Silico investigation on the interaction of a thymine-bearing tetrapeptide with a homoadenine DNA. J. Mol. Liq. 2022, 347, 117975. [Google Scholar] [CrossRef]
  38. Roviello, G.N.; Roviello, G.; Musumeci, D.; Bucci, E.M.; Pedone, C. Dakin–West reaction on 1-thyminyl acetic acid for the synthesis of 1, 3-bis (1-thyminyl)-2-propanone, a heteroaromatic compound with nucleopeptide-binding properties. Amino Acids 2012, 43, 1615–1623. [Google Scholar] [CrossRef]
  39. Roviello, G.N.; Gaetano, S.D.; Capasso, D.; Cesarani, A.; Bucci, E.M.; Pedone, C. Synthesis, spectroscopic studies and biological activity of a novel nucleopeptide with Moloney murine leukemia virus reverse transcriptase inhibitory activity. Amino Acids 2010, 38, 1489–1496. [Google Scholar] [CrossRef]
  40. Moretta, R.; Terracciano, M.; Borbone, N.; Oliviero, G.; Schiattarella, C.; Piccialli, G.; Falanga, A.P.; Marzano, M.; Dardano, P.; De Stefano, L. PNA-based graphene oxide/porous silicon hybrid biosensor: Towards a label-free optical assay for brugada syndrome. Nanomaterials 2020, 10, 2233. [Google Scholar] [CrossRef]
  41. Zarrilli, F.; Amato, F.; Morgillo, C.M.; Pinto, B.; Santarpia, G.; Borbone, N.; D’Errico, S.; Catalanotti, B.; Piccialli, G.; Castaldo, G. Peptide nucleic acids as miRNA target protectors for the treatment of cystic fibrosis. Molecules 2017, 22, 1144. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Roviello, G.N.; Oliviero, G.; Di Napoli, A.; Borbone, N.; Piccialli, G. Synthesis, self-assembly-behavior and biomolecular recognition properties of thyminyl dipeptides. Arab. J. Chem. 2020, 13, 1966–1974. [Google Scholar] [CrossRef]
  43. Crisci, T.; Falanga, A.P.; Casalino, M.; Borbone, N.; Terracciano, M.; Chianese, G.; Gioffrè, M.; D’Errico, S.; Marzano, M.; Rea, I. Bioconjugation of a PNA Probe to Zinc Oxide Nanowires for Label-Free Sensing. Nanomaterials 2021, 11, 523. [Google Scholar] [CrossRef] [PubMed]
  44. Bertucci, A.; Silvestrini, S.; Corradini, R.; Cola, L.D. Loading of PNA and other molecular payloads on inorganic nanostructures for theranostics. In DNA Nanotechnology. Methods in Molecular Biology; Zuccheri, G., Ed.; Humana Press: New York, NY, USA, 2018; Volume 1811, pp. 65–77. [Google Scholar]
  45. Bertucci, A.; Prasetyanto, E.A.; Septiadi, D.; Manicardi, A.; Brognara, E.; Gambari, R.; Corradini, R.; De Cola, L. Combined delivery of temozolomide and anti-miR221 PNA using mesoporous silica nanoparticles induces apoptosis in resistant glioma cells. Small 2015, 11, 5687–5695. [Google Scholar] [CrossRef]
  46. Falanga, A.P.; Cerullo, V.; Marzano, M.; Feola, S.; Oliviero, G.; Piccialli, G.; Borbone, N. Peptide nucleic acid-functionalized adenoviral vectors targeting G-quadruplexes in the P1 promoter of Bcl-2 proto-oncogene: A new tool for gene modulation in anticancer therapy. Bioconj. Chem. 2019, 30, 572–582. [Google Scholar] [CrossRef]
  47. Amato, F.; Tomaiuolo, R.; Nici, F.; Borbone, N.; Elce, A.; Catalanotti, B.; D’Errico, S.; Morgillo, C.M.; De Rosa, G.; Mayol, L. Exploitation of a very small peptide nucleic acid as a new inhibitor of miR-509-3p involved in the regulation of cystic fibrosis disease-gene expression. BioMed Res. Int. 2014, 2014, 610718. [Google Scholar] [CrossRef]
  48. Amato, J.; Stellato, M.I.; Pizzo, E.; Petraccone, L.; Oliviero, G.; Borbone, N.; Piccialli, G.; Orecchia, A.; Bellei, B.; Castiglia, D. PNA as a potential modulator of COL7A1 gene expression in dominant dystrophic epidermolysis bullosa: A physico-chemical study. Mol. Biosyst. 2013, 9, 3166–3174. [Google Scholar] [CrossRef]
  49. Smith, C.E.; Zain, R. Therapeutic oligonucleotides: State of the art. Annu. Rev. Pharmacol. 2019, 59, 605–630. [Google Scholar] [CrossRef]
  50. Byun, J. Recent progress and opportunities for nucleic acid aptamers. Life 2021, 11, 193. [Google Scholar] [CrossRef]
  51. Afrasiabi, S.; Pourhajibagher, M.; Raoofian, R.; Tabarzad, M.; Bahador, A. Therapeutic applications of nucleic acid aptamers in microbial infections. J. Biomed. Sci. 2020, 27, 6. [Google Scholar] [CrossRef]
  52. Shrivastava, G.; Bakshi, H.A.; Aljabali, A.A.; Mishra, V.; Hakkim, F.L.; Charbe, N.B.; Kesharwani, P.; Chellappan, D.K.; Dua, K.; Tambuwala, M.M. Nucleic acid aptamers as a potential nucleus targeted drug delivery system. Curr. Drug Deliv. 2020, 17, 101–111. [Google Scholar] [CrossRef] [PubMed]
  53. Li, L.; Xu, S.; Yan, H.; Li, X.; Yazd, H.S.; Li, X.; Huang, T.; Cui, C.; Jiang, J.; Tan, W. Nucleic acid aptamers for molecular diagnostics and therapeutics: Advances and perspectives. Angew. Chem. Int. Ed. 2021, 60, 2221–2231. [Google Scholar] [CrossRef]
  54. Cai, S.; Yan, J.; Xiong, H.; Liu, Y.; Peng, D.; Liu, Z. Investigations on the interface of nucleic acid aptamers and binding targets. Analyst 2018, 143, 5317–5338. [Google Scholar] [CrossRef] [PubMed]
  55. Zamay, T.N.; Zamay, G.S.; Shnayder, N.A.; Dmitrenko, D.V.; Zamay, S.S.; Yushchenko, V.; Kolovskaya, O.S.; Susevski, V.; Berezovski, M.V.; Kichkailo, A.S. Nucleic acid aptamers for molecular therapy of epilepsy and blood-brain barrier damages. Mol. Ther-Nucl. Acids 2020, 19, 157–167. [Google Scholar] [CrossRef] [PubMed]
  56. Hassanzadeh, L.; Chen, S.; Veedu, R.N. Radiolabeling of nucleic acid aptamers for highly sensitive disease-specific molecular imaging. Pharmaceuticals 2018, 11, 106. [Google Scholar] [CrossRef] [Green Version]
  57. Bruno, J.G. Potential inherent stimulation of the innate immune system by nucleic acid aptamers and possible corrective approaches. Pharmaceuticals 2018, 11, 62. [Google Scholar] [CrossRef] [Green Version]
  58. Zhao, Q.; Tao, J.; Uppal, J.S.; Peng, H.; Wang, H.; Le, X.C. Nucleic acid aptamers improving fluorescence anisotropy and fluorescence polarization assays for small molecules. TrAC Trend. Anal. Chem. 2019, 110, 401–409. [Google Scholar] [CrossRef]
  59. Lei, Y.; He, X.; Tang, J.; Shi, H.; He, D.; Liu, J.; Zeng, Y.; Wang, K. Ultra-pH-responsive split i-motif based aptamer anchoring strategy for specific activatable imaging of acidic tumor microenvironment. Chem. Commun. 2018, 54, 10288–10291. [Google Scholar] [CrossRef]
  60. Amato, J.; D’Aria, F.; Marzano, S.; Iaccarino, N.; Randazzo, A.; Giancola, C.; Pagano, B. On the thermodynamics of folding of an i-motif DNA in solution under favorable conditions. Phys. Chem. Chem. Phys. 2021, 23, 15030–15037. [Google Scholar] [CrossRef]
  61. Rusciano, G.; De Luca, A.C.; Pesce, G.; Sasso, A.; Oliviero, G.; Amato, J.; Borbone, N.; D’Errico, S.; Piccialli, V.; Piccialli, G. Label-free probing of G-quadruplex formation by surface-enhanced Raman scattering. Anal. Chem. 2011, 83, 6849–6855. [Google Scholar] [CrossRef]
  62. Borbone, N.; Amato, J.; Oliviero, G.; D’Atri, V.; Gabelica, V.; De Pauw, E.; Piccialli, G.; Mayol, L. d (CGGTGGT) forms an octameric parallel G-quadruplex via stacking of unusual G (: C): G (: C): G (: C): G (: C) octads. Nucleic Acids Res. 2011, 39, 7848–7857. [Google Scholar] [CrossRef]
  63. Marzano, M.; Falanga, A.P.; Marasco, D.; Borbone, N.; D’Errico, S.; Piccialli, G.; Roviello, G.N.; Oliviero, G. Evaluation of an analogue of the marine ε-PLL peptide as a ligand of G-quadruplex DNA structures. Mar. Drugs 2020, 18, 49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Oliviero, G.; Amato, J.; Borbone, N.; D’Errico, S.; Galeone, A.; Mayol, L.; Haider, S.; Olubiyi, O.; Hoorelbeke, B.; Balzarini, J. Tetra-end-linked oligonucleotides forming DNA G-quadruplexes: A new class of aptamers showing anti-HIV activity. Chem. Commun. 2010, 46, 8971–8973. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Nici, F.; Oliviero, G.; Falanga, A.; D’Errico, S.; Marzano, M.; Musumeci, D.; Montesarchio, D.; Noppen, S.; Pannecouque, C.; Piccialli, G. Anti-HIV activity of new higher order G-quadruplex aptamers obtained from tetra-end-linked oligonucleotides. Org. Biomol. Chem. 2018, 16, 2349–2355. [Google Scholar] [CrossRef] [PubMed]
  66. Li, T.; Shi, L.; Wang, E.; Dong, S. Multifunctional G-quadruplex aptamers and their application to protein detection. Chem Eur. J. 2009, 15, 1036–1042. [Google Scholar] [CrossRef] [PubMed]
  67. Tucker, W.O.; Shum, K.T.; Tanner, J.A. G-quadruplex DNA aptamers and their ligands: Structure, function and application. Curr. Pharm. Design 2012, 18, 2014–2026. [Google Scholar] [CrossRef] [Green Version]
  68. Platella, C.; Riccardi, C.; Montesarchio, D.; Roviello, G.N.; Musumeci, D. G-quadruplex-based aptamers against protein targets in therapy and diagnostics. BBA Gen. Subj. 2017, 1861, 1429–1447. [Google Scholar] [CrossRef]
  69. Umar, M.I.; Ji, D.; Chan, C.-Y.; Kwok, C.K. G-quadruplex-based fluorescent turn-on ligands and aptamers: From development to applications. Molecules 2019, 24, 2416. [Google Scholar] [CrossRef] [Green Version]
  70. Ghahremanpour, M.M.; Tirado-Rives, J.; Deshmukh, M.; Ippolito, J.A.; Zhang, C.-H.; Cabeza de Vaca, I.; Liosi, M.-E.; Anderson, K.S.; Jorgensen, W.L. Identification of 14 known drugs as inhibitors of the main protease of SARS-CoV-2. ACS Med. Chem. Lett. 2020, 11, 2526–2533. [Google Scholar] [CrossRef]
  71. Amin, S.A.; Banerjee, S.; Ghosh, K.; Gayen, S.; Jha, T. Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors. Bioorg. Med. Chem. 2021, 29, 115860. [Google Scholar] [CrossRef]
  72. Haniff, H.S.; Tong, Y.; Liu, X.; Chen, J.L.; Suresh, B.M.; Andrews, R.J.; Peterson, J.M.; O’Leary, C.A.; Benhamou, R.I.; Moss, W.N. Targeting the SARS-CoV-2 RNA genome with small molecule binders and ribonuclease targeting chimera (RIBOTAC) degraders. ACS Cent. Sci. 2020, 6, 1713–1721. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, K.; Zheludev, I.N.; Hagey, R.J.; Wu, M.T.-P.; Haslecker, R.; Hou, Y.J.; Kretsch, R.; Pintilie, G.D.; Rangan, R.; Kladwang, W.; et al. Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome. Nat. Struct. Mol. Biol. 2021, 28, 747–754. [Google Scholar] [CrossRef] [PubMed]
  74. Van Riel, D.; de Wit, E. Next-generation vaccine platforms for COVID-19. Nat. Mater. 2020, 19, 810–812. [Google Scholar] [CrossRef] [PubMed]
  75. Pascolo, S. Vaccines against COVID-19: Priority to mRNA-Based Formulations. Cells 2021, 10, 2716. [Google Scholar] [CrossRef] [PubMed]
  76. Mahase, E. Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant. BMJ 2021, 372, n296. [Google Scholar] [CrossRef]
  77. Li, Y.-D.; Chi, W.-Y.; Su, J.-H.; Ferrall, L.; Hung, C.-F.; Wu, T.-C. Coronavirus vaccine development: From SARS and MERS to COVID-19. J. Biomed. Sci. 2020, 27, 104. [Google Scholar] [CrossRef]
  78. Järås, M.; Edqvist, A.; Rebetz, J.; Salford, L.G.; Widegren, B.; Fan, X. Human short-term repopulating cells have enhanced telomerase reverse transcriptase expression. Blood 2006, 108, 1084–1091. [Google Scholar] [CrossRef] [Green Version]
  79. Su, Y.; Ghodke, P.P.; Egli, M.; Li, L.; Wang, Y.; Guengerich, F.P. Human DNA polymerase η has reverse transcriptase activity in cellular environments. J. Biol. Chem. 2019, 294, 6073–6081. [Google Scholar] [CrossRef] [Green Version]
  80. Schwertz, H.; Rowley, J.W.; Schumann, G.G.; Thorack, U.; Campbell, R.A.; Manne, B.K.; Zimmerman, G.A.; Weyrich, A.S.; Rondina, M.T. Endogenous LINE-1 (Long Interspersed Nuclear Element-1) reverse transcriptase activity in platelets controls translational events through RNA–DNA hybrids. Arterioscl. Throm. Vas. 2018, 38, 801–815. [Google Scholar] [CrossRef]
  81. Cimolai, N. Do RNA vaccines obviate the need for genotoxicity studies? Mutagenesis 2020, 35, 509–510. [Google Scholar] [CrossRef]
  82. Domazet-Lošo, T. mRNA vaccines: Why is the biology of retroposition ignored? OSF Prepr. 2021, in press. [Google Scholar] [CrossRef]
  83. Udroiu, C.M.; Mota-Babiloni, A.; Espinós-Estévez, C.; Navarro-Esbrí, J. Energy-Efficient Technologies for Ultra-Low Temperature Refrigeration. In Smart and Sustainable Technology for Resilient Cities and Communities. Advances in Sustainability Science and Technology; Howlett, R.J., Jain, L.C., Littlewood, J.R., Balas, M.M., Eds.; Springer: Singapore, 2022. [Google Scholar] [CrossRef]
  84. Chen, S.; Evert, B.; Adeniyi, A.; Salla-Martret, M.; Lua, L.H.L.; Ozberk, V.; Pandey, M.; Good, M.F.; Suhrbier, A.; Halfmann, P.; et al. Ambient Temperature Stable, Scalable COVID-19 Polymer Particle Vaccines Induce Protective Immunity. Adv. Healthc. Mater. 2021, 11, 2102089. [Google Scholar] [CrossRef] [PubMed]
  85. Al Bahrani, S.; Albarrak, A.; Alghamdi, O.A.; Alghamdi, M.A.; Hakami, F.H.; Al Abaadi, A.K.; Alkhrashi, S.A.; Alghamdi, M.Y.; Almershad, M.M.; Alenazi, M.M. Safety and reactogenicity of the ChAdOx1 (AZD1222) COVID-19 vaccine in Saudi Arabia. Int. J. Infect. Dis. 2021, 110, 359–362. [Google Scholar] [CrossRef] [PubMed]
  86. World Health Organization. AstraZeneca ChAdOx1-S/nCoV-19 [Recombinant], COVID-19 Vaccine. Available online: https://www.who.int/publications/m/item/chadox1-s-recombinant-covid-19-vaccine (accessed on 8 April 2022).
  87. Sah, R.; Shrestha, S.; Mehta, R.; Sah, S.K.; Raaban, A.R.; Dharma, K.; Rodriguez-Morales, A.J. AZD1222 (Covishield) vaccination for COVID-19: Experiences, challenges and solutions in Nepal. Travel Med. Infect. Di. 2021, 40, 101989. [Google Scholar] [CrossRef]
  88. Simnani, F.Z.; Singh, D.; Kaur, R. COVID-19 phase 4 vaccine candidates, effectiveness on SARS-CoV-2 variants, neutralizing antibody, rare side effects, traditional and nano-based vaccine platforms: A review. 3 Biotech 2022, 12, 15. [Google Scholar] [CrossRef]
  89. Schoenmaker, L.; Witzigmann, D.; Kulkarni, J.A.; Verbeke, R.; Kersten, G.; Jiskoot, W.; Crommelin, D.J. mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. Int. J. Pharmaceut. 2021, 601, 120586. [Google Scholar] [CrossRef]
  90. Hassett, K.J.; Higgins, J.; Woods, A.; Levy, B.; Xia, Y.; Hsiao, C.J.; Acosta, E.; Almarsson, Ö.; Moore, M.J.; Brito, L.A. Impact of lipid nanoparticle size on mRNA vaccine immunogenicity. J. Control. Release 2021, 335, 237–246. [Google Scholar] [CrossRef]
  91. Kon, E.; Elia, U.; Peer, D. Principles for designing an optimal mRNA lipid nanoparticle vaccine. Curr. Opin. Biotech. 2022, 73, 329–336. [Google Scholar] [CrossRef]
  92. Knudson, C.J.; Alves-Peixoto, P.; Muramatsu, H.; Stotesbury, C.; Tang, L.; Lin, P.J.; Tam, Y.K.; Weissman, D.; Pardi, N.; Sigal, L.J. Lipid-nanoparticle-encapsulated mRNA vaccines induce protective memory CD8 T cells against a lethal viral infection. Mol. Ther. 2021, 29, 2769–2781. [Google Scholar] [CrossRef]
  93. Hassett, K.J.; Benenato, K.E.; Jacquinet, E.; Lee, A.; Woods, A.; Yuzhakov, O.; Himansu, S.; Deterling, J.; Geilich, B.M.; Ketova, T. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucl. Acids 2019, 15, 1–11. [Google Scholar] [CrossRef] [Green Version]
  94. Strizova, Z.; Smetanova, J.; Bartunkova, J.; Milota, T. Principles and challenges in anti-COVID-19 vaccine development. Int. Arch. Allergy Imm. 2021, 182, 339–349. [Google Scholar] [CrossRef]
  95. Park, J.W.; Lagniton, P.N.; Liu, Y.; Xu, R.-H. mRNA vaccines for COVID-19: What, why and how. Int. J. Biol. Sci. 2021, 17, 1446. [Google Scholar] [CrossRef] [PubMed]
  96. Granados-Riveron, J.T.; Aquino-Jarquin, G. Engineering of the current nucleoside-modified mRNA-LNP vaccines against SARS-CoV-2. Biomed. Pharmacother. 2021, 142, 111953. [Google Scholar] [CrossRef] [PubMed]
  97. Ouranidis, A.; Vavilis, T.; Mandala, E.; Davidopoulou, C.; Stamoula, E.; Markopoulou, C.K.; Karagianni, A.; Kachrimanis, K. mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles. Biomedicines 2022, 10, 50. [Google Scholar] [CrossRef] [PubMed]
  98. Teo, S.P. Review of COVID-19 vaccines and their evidence in older adults. Ann. Geriatr. Med. Res. 2021, 25, 4–9. [Google Scholar] [CrossRef] [PubMed]
  99. Minnaert, A.-K.; Vanluchene, H.; Verbeke, R.; Lentacker, I.; De Smedt, S.C.; Raemdonck, K.; Sanders, N.N.; Remaut, K. Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across. Adv. Drug Deliver. Rev. 2021, 176, 113900. [Google Scholar] [CrossRef]
  100. Miao, L.; Zhang, Y.; Huang, L. mRNA vaccine for cancer immunotherapy. Mol. Cancer 2021, 20, 41. [Google Scholar] [CrossRef]
  101. Furuichi, Y. Discovery of m7G-cap in eukaryotic mRNAs. Proc. Jpn. Acad. Ser. B 2015, 91, 394–409. [Google Scholar] [CrossRef] [Green Version]
  102. Mattijssen, S.; Kozlov, G.; Fonseca, B.D.; Gehring, K.; Maraia, R.J. LARP1 and LARP4: Up close with PABP for mRNA 3′poly (A) protection and stabilization. RNA Biol. 2021, 18, 259–274. [Google Scholar] [CrossRef]
  103. Sachs, A. The role of poly (A) in the translation and stability of mRNA. Curr. Opin. Cell Biol. 1990, 2, 1092–1098. [Google Scholar] [CrossRef]
  104. Suzuki, Y.; Ishihara, H. Difference in the lipid nanoparticle technology employed in three approved siRNA (Patisiran) and mRNA (COVID-19 vaccine) drugs. Drug Metab. Pharmok. 2021, 41, 100424. [Google Scholar] [CrossRef] [PubMed]
  105. Zohra, F.T.; Chowdhury, E.H.; Akaike, T. High performance mRNA transfection through carbonate apatite–cationic liposome conjugates. Biomaterials 2009, 30, 4006–4013. [Google Scholar] [CrossRef] [PubMed]
  106. Pardi, N.; Tuyishime, S.; Muramatsu, H.; Kariko, K.; Mui, B.L.; Tam, Y.K.; Madden, T.D.; Hope, M.J.; Weissman, D. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release 2015, 217, 345–351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Calina, D.; Hernández, A.F.; Hartung, T.; Egorov, A.M.; Izotov, B.N.; Nikolouzakis, T.K.; Tsatsakis, A.; Vlachoyiannopoulos, P.G.; Docea, A.O. Challenges and scientific prospects of the newest generation of mRNA-based vaccines against SARS-CoV-2. Life 2021, 11, 907. [Google Scholar] [CrossRef]
  108. Kostarelos, K. Nanoscale nights of COVID-19. Nat. Nanotechnol. 2020, 15, 343–344. [Google Scholar] [CrossRef]
  109. Corbett, K.S.; Edwards, D.K.; Leist, S.R.; Abiona, O.M.; Boyoglu-Barnum, S.; Gillespie, R.A.; Himansu, S.; Schäfer, A.; Ziwawo, C.T.; DiPiazza, A.T. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 2020, 586, 567–571. [Google Scholar] [CrossRef]
  110. Eygeris, Y.; Patel, S.; Jozic, A.; Sahay, G. Deconvoluting lipid nanoparticle structure for messenger RNA delivery. Letter 2020, 20, 4543–4549. [Google Scholar] [CrossRef]
  111. Zare, M.; Sillanpää, M.; Ramakrishna, S. Essential role of quantum science and nanoscience in antiviral strategies for COVID-19. Mater. Adv. 2021, 2, 2188–2199. [Google Scholar] [CrossRef]
  112. Tan, T.K.; Rijal, P.; Rahikainen, R.; Keeble, A.H.; Schimanski, L.; Hussain, S.; Harvey, R.; Hayes, J.W.; Edwards, J.C.; McLean, R.K. A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses. Nat. Commun. 2021, 12, 542. [Google Scholar] [CrossRef]
  113. Goodsell, D.S.; Burley, S.K. RCSB Protein Data Bank resources for structure-facilitated design of mRNA vaccines for existing and emerging viral pathogens. Structure 2022, 30, 55–68. [Google Scholar] [CrossRef]
  114. Lee, J.; Song, J.-U.; Shim, S.R. Comparing the diagnostic accuracy of rapid antigen detection tests to real time polymerase chain reaction in the diagnosis of SARS-CoV-2 infection: A systematic review and meta-analysis. J. Clin. Virol. 2021, 144, 104985. [Google Scholar] [CrossRef] [PubMed]
  115. Cubas-Atienzar, A.I.; Kontogianni, K.; Edwards, T.; Wooding, D.; Buist, K.; Thompson, C.R.; Williams, C.T.; Patterson, E.I.; Hughes, G.L.; Baldwin, L.; et al. Limit of detection in different matrices of 19 commercially available rapid antigen tests for the detection of SARS-CoV-2. Sci. Rep. 2021, 11, 18313. [Google Scholar] [CrossRef] [PubMed]
  116. Kong, D.; Wang, X.; Gu, C.; Guo, M.; Wang, Y.; Ai, Z.; Zhang, S.; Chen, Y.; Liu, W.; Wu, Y. Direct SARS-CoV-2 Nucleic Acid Detection by Y-Shaped DNA Dual-Probe Transistor Assay. J. Am. Chem. Soc. 2021, 143, 17004–17014. [Google Scholar] [CrossRef]
  117. Nascimento Junior, J.A.C.; Santos, A.M.; Quintans-Junior, L.J.; Walker, C.I.B.; Borges, L.P.; Serafini, M.R. SARS, MERS and SARS-CoV-2 (COVID-19) treatment: A patent review. Expert Opin. Ther. Pat. 2020, 30, 567–579. [Google Scholar] [CrossRef] [PubMed]
  118. Quemener, A.M.; Galibert, M.D. Antisense oligonucleotide: A promising therapeutic option to beat COVID-19. WIREs RNA, 2021; in press. [Google Scholar] [CrossRef]
  119. Huston, N.C.; Wan, H.; Strine, M.S.; Tavares, R.d.C.A.; Wilen, C.B.; Pyle, A.M. Comprehensive in vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms. Mol. Cell 2021, 81, 584–598. [Google Scholar] [CrossRef]
  120. Lulla, V.; Wandel, M.P.; Bandyra, K.J.; Ulferts, R.; Wu, M.; Dendooven, T.; Yang, X.; Doyle, N.; Oerum, S.; Beale, R. Targeting the conserved stem loop 2 motif in the SARS-CoV-2 genome. J. Virol. 2021, 95, e00663. [Google Scholar] [CrossRef]
  121. Sun, L.; Li, P.; Ju, X.; Rao, J.; Huang, W.; Ren, L.; Zhang, S.; Xiong, T.; Xu, K.; Zhou, X. In vivo structural characterization of the SARS-CoV-2 RNA genome identifies host proteins vulnerable to repurposed drugs. Cell 2021, 184, 1865–1883. [Google Scholar] [CrossRef]
  122. Wan, Q.; Liu, X.; Zu, Y. Oligonucleotide aptamers for pathogen detection and infectious disease control. Theranostics 2021, 11, 9133. [Google Scholar] [CrossRef]
  123. Sun, H.; Zhu, X.; Lu, P.Y.; Rosato, R.R.; Tan, W.; Zu, Y. Oligonucleotide aptamers: New tools for targeted cancer therapy. Mol. Ther Nucl. Acids 2014, 3, e182. [Google Scholar] [CrossRef]
  124. Li, J.; Sczepanski, J.T. Targeting a conserved structural element from the SARS-CoV-2 genome using l-DNA aptamers. RSC Chem. Biol. 2022, 3, 79–84. [Google Scholar] [CrossRef] [PubMed]
  125. Lipps, H.J.; Rhodes, D. G-quadruplex structures: In vivo evidence and function. Trends Cell Biol. 2009, 19, 414–422. [Google Scholar] [CrossRef] [PubMed]
  126. Xi, H.; Juhas, M.; Zhang, Y. G-quadruplex based biosensor: A potential tool for SARS-CoV-2 detection. Biosens. Bioelectron. 2020, 167, 112494. [Google Scholar] [CrossRef] [PubMed]
Ijms 23 04359 g001a 550Ijms 23 04359 g001b 550
Figure 1. (a) The 28-kDa highly conserved FSE (frameshift stimulation element, PDB ID: 6XRZ https://www.rcsb.org/3d-view/6XRZ/1 accessed on 4 February 2022) of the SARS-CoV-2 genome is an example of a potential candidate for targeting by small molecules and oligonucleotides as it is required for the balanced expression of SARS-CoV-2 proteins [73]. (b) An example of quadruple helical DNA (a monomeric parallel-stranded quadruplex in human VEGF promoter; PDB ID: 2M27 https://www.rcsb.org/3d-view/2M27/0 accessed on 1 April 2022; left) with a schematic representation of a G4 quartet (middle); and a complex between a nucleic acid aptamer (RNA-aptamer K1; purple) with its protein target (Tetracycline repressor protein; PDB ID: 6SY4 https://www.rcsb.org/3d-sequence/6SY4?assemblyId=1 accessed on 1 April 2022; right).
Figure 1. (a) The 28-kDa highly conserved FSE (frameshift stimulation element, PDB ID: 6XRZ https://www.rcsb.org/3d-view/6XRZ/1 accessed on 4 February 2022) of the SARS-CoV-2 genome is an example of a potential candidate for targeting by small molecules and oligonucleotides as it is required for the balanced expression of SARS-CoV-2 proteins [73]. (b) An example of quadruple helical DNA (a monomeric parallel-stranded quadruplex in human VEGF promoter; PDB ID: 2M27 https://www.rcsb.org/3d-view/2M27/0 accessed on 1 April 2022; left) with a schematic representation of a G4 quartet (middle); and a complex between a nucleic acid aptamer (RNA-aptamer K1; purple) with its protein target (Tetracycline repressor protein; PDB ID: 6SY4 https://www.rcsb.org/3d-sequence/6SY4?assemblyId=1 accessed on 1 April 2022; right).
Ijms 23 04359 g001aIjms 23 04359 g001b
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Figure 2. Chemical representations of some typical components of lipid nanoparticles as well as specific components of the Moderna vaccine. DPPC: dipalmitoylphosphatidylcholine; DSPC: distearoylphosphatidylcholine.
Figure 2. Chemical representations of some typical components of lipid nanoparticles as well as specific components of the Moderna vaccine. DPPC: dipalmitoylphosphatidylcholine; DSPC: distearoylphosphatidylcholine.
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Figure 3. Schematic representation of some typical modifications of synthetic mRNAs contained in the COVID-19 vaccines: (a) 5′ capping via cap1 structure (m7GpppNm); (b) uridines are replaced with pseudouridine or 1-methyl pseudouridine units.
Figure 3. Schematic representation of some typical modifications of synthetic mRNAs contained in the COVID-19 vaccines: (a) 5′ capping via cap1 structure (m7GpppNm); (b) uridines are replaced with pseudouridine or 1-methyl pseudouridine units.
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Figure 4. Structures of nanoparticles used for COVID-19 vaccine candidates: (a) mRNA vaccines realized for the COVID-19 pandemic are composed of long strands of RNAs (magenta) that encode the SARS-CoV-2 S protein enclosed in lipids (cyan), connected with lipids conjugated to polyethylene glycol (PEG) chains (green), that deliver the RNA cargo into recipient cells. In the idealized illustration by David S. Goodsell, RCSB Protein Data Bank [113], the lipids are arranged in a simplified model of a circular bilayer surrounding the mRNAs, and the PEG chains are endowed with both folded and extended conformations. Note how the real structure may be less regular, as suggested in the literature [110]. (b) An example of protein nanoparticle-based vaccine proposed against SARS-CoV-2. It displays the S glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle platform, SpyCatcher003-mi3, and uses SpyTag/SpyCatcher technology [112] (https://www.rcsb.org/structure/7B3Y, accessed on 4 February 2022).
Figure 4. Structures of nanoparticles used for COVID-19 vaccine candidates: (a) mRNA vaccines realized for the COVID-19 pandemic are composed of long strands of RNAs (magenta) that encode the SARS-CoV-2 S protein enclosed in lipids (cyan), connected with lipids conjugated to polyethylene glycol (PEG) chains (green), that deliver the RNA cargo into recipient cells. In the idealized illustration by David S. Goodsell, RCSB Protein Data Bank [113], the lipids are arranged in a simplified model of a circular bilayer surrounding the mRNAs, and the PEG chains are endowed with both folded and extended conformations. Note how the real structure may be less regular, as suggested in the literature [110]. (b) An example of protein nanoparticle-based vaccine proposed against SARS-CoV-2. It displays the S glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle platform, SpyCatcher003-mi3, and uses SpyTag/SpyCatcher technology [112] (https://www.rcsb.org/structure/7B3Y, accessed on 4 February 2022).
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Figure 5. Structures of nucleic acid analog [PMO (morpholino), P-PMO (peptide-morpholino), LNA (locked nucleic acid)] moieties and modifications of the nucleic acid backbone [PS (phosphorothioate), 2′-MOE (2′-methyl O-ester)] employed in the antisense strategies against SARS-CoV-2.
Figure 5. Structures of nucleic acid analog [PMO (morpholino), P-PMO (peptide-morpholino), LNA (locked nucleic acid)] moieties and modifications of the nucleic acid backbone [PS (phosphorothioate), 2′-MOE (2′-methyl O-ester)] employed in the antisense strategies against SARS-CoV-2.
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Table
Table 1. Some of the most used nucleic acid-based vaccines in Western countries.
Table 1. Some of the most used nucleic acid-based vaccines in Western countries.
Vaccine NameCarried Nucleic AcidDeveloperConfirmed Efficacy
ChAdOx1-S/AZD1222DNAAstraZeneca + University of Oxford63.1%, based on a median follow-up of 80 days
Ad26.CoV2.SDNAJanssen Pharmaceuticals Johnson & Johnson66.0%, 28 days post-vaccination
BNT162/ComirnatyRNAPfizer/BioNTech + Fosun Pharma 95.0%, measured starting from seven days after the second dose
mRNA-1273RNAModerna + National Institute of Allergy and Infectious Diseases (NIAID)94.1%, measured starting from two weeks after the second dose
Table
Table 2. Some of the most used nucleic acid analogs (NAA) and their main anti-SARS-CoV-2 applications.
Table 2. Some of the most used nucleic acid analogs (NAA) and their main anti-SARS-CoV-2 applications.
NAAFull NamePropertiesReference
PMO/P-PMOMorpholino/peptide-morpholinoTargeting RNA genome/regulatory sequences/very high nuclease stability[118]
LNALocked nucleic acidDisrupting RNA secondary structure/provoking steric blocks/very high nuclease stability[119,120]
2′-MOE2′-Methyl O-estersDisrupting interactions between host proteins and SARS-CoV-2 RNA/provoking steric blocks/high nuclease stability[121]
PSPhosphorothioatesDisrupting interactions between host proteins and SARS-CoV-2 RNA/provoking steric blocks/high nuclease stability[121]
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Borbone, N.; Piccialli, I.; Falanga, A.P.; Piccialli, V.; Roviello, G.N.; Oliviero, G. Nucleic Acids as Biotools at the Interface between Chemistry and Nanomedicine in the COVID-19 Era. Int. J. Mol. Sci. 2022, 23, 4359. https://doi.org/10.3390/ijms23084359

AMA Style

Borbone N, Piccialli I, Falanga AP, Piccialli V, Roviello GN, Oliviero G. Nucleic Acids as Biotools at the Interface between Chemistry and Nanomedicine in the COVID-19 Era. International Journal of Molecular Sciences. 2022; 23(8):4359. https://doi.org/10.3390/ijms23084359

Chicago/Turabian Style

Borbone, Nicola, Ilaria Piccialli, Andrea Patrizia Falanga, Vincenzo Piccialli, Giovanni N. Roviello, and Giorgia Oliviero. 2022. "Nucleic Acids as Biotools at the Interface between Chemistry and Nanomedicine in the COVID-19 Era" International Journal of Molecular Sciences 23, no. 8: 4359. https://doi.org/10.3390/ijms23084359

APA Style

Borbone, N., Piccialli, I., Falanga, A. P., Piccialli, V., Roviello, G. N., & Oliviero, G. (2022). Nucleic Acids as Biotools at the Interface between Chemistry and Nanomedicine in the COVID-19 Era. International Journal of Molecular Sciences, 23(8), 4359. https://doi.org/10.3390/ijms23084359

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