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Pharmaceuticals
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Small Molecules Targeting Viral Polymerases
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Small Molecules Targeting Viral Polymerases

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (25 March 2024) | Viewed by 19576

Special Issue Editors

Dr. Maria Letizia Barreca

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, via Fabretti 48, 06123 Perugia, Italy
Interests: medicinal chemistry; computer-aided drug discovery; anti-infective and neurodegenerative diseases; cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Astolfi

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, via Fabretti 48, 06123 Perugia, Italy
Interests: medicinal chemistry; computer-aided drug discovery; anti-infective agents; kinase inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The magnitude of the sudden and unpredictable COVID-19 pandemic has drawn global attention to both new and re-emerging viruses as pathogens responsible for current and future health threats. In addition, the development of resistance against antiviral drugs used in therapy for established viruses represents one of the major challenges of healthcare. 

Thus, there is a pressing need to find efficacious novel drugs to treat viral diseases. In this context, the discovery and development of small molecules targeting viral polymerases is a field of great interest. Indeed, these enzymes are attractive targets for the identification of effective antiviral drugs as they lack mammalian homologs and are central components in the life cycles of viruses, playing a key role in viral genome replication and transcription. As a successful example, Remdesevir and Molnupiravir—both recently approved by the U.S. Food and Drug Administration for emergency use to treat COVID-19—are small-molecule inhibitors of SARS-COV-2 RNA-dependent RNA polymerase.

Furthermore, viral polymerases offer promising opportunities to combat multiple viral pathogens through the development of broad-spectrum antivirals as the structures of these essential enzymes are comparatively well conserved across viral classes. It is also noteworthy that intensive structural and functional studies of viral polymerases have been reported over the years, offering new avenues for the rational discovery of more effective antiviral agents.

In this Special Issue entitled “Small molecules targeting viral polymerases”, Pharmaceuticals welcomes high-quality reviews and original research articles focused on the investigation of novel small molecules targeting viral polymerases, as well as on structural and functional studies aimed at increasing the knowledge on these key enzymes.

Dr. Maria Letizia Barreca
Dr. Andrea Astolfi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • small molecules
  • antiviral agents
  • viruses
  • RNA-dependent RNA polymerase
  • RNA-dependent DNA polymerase
  • DNA-dependent DNA polymerase
  • inhibitors
  • drug design
  • computer-aided drug discovery
  • drug repositioning
  • emerging diseases
  • infectious diseases
  • drug resistance
  • broad-spectrum antivirals

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Published Papers (7 papers)

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Research

Jump to: Review

14 pages, 5370 KiB  
Article
Synthesis and Antiviral Activity of Novel β-D-N4-Hydroxycytidine Ester Prodrugs as Potential Compounds for the Treatment of SARS-CoV-2 and Other Human Coronaviruses
by Elizaveta S. Darnotuk, Andrei E. Siniavin, Natal’ya S. Shastina, Sergey I. Luyksaar, Anna M. Inshakova, Natalia E. Bondareva, Sergey A. Zolotov, Nadezhda L. Lubenec, Anna B. Sheremet, Denis Y. Logunov, Nailya A. Zigangirova, Vladimir A. Gushchin and Alexander L. Gintsburg
Pharmaceuticals 2024, 17(1), 35; https://doi.org/10.3390/ph17010035 - 26 Dec 2023
Cited by 2 | Viewed by 1808
Abstract
The spread of COVID-19 infection continues due to the emergence of multiple transmissible and immune-evasive variants of the SARS-CoV-2 virus. Although various vaccines have been developed and several drugs have been approved for the treatment of COVID-19, the development of new drugs to [...] Read more.
The spread of COVID-19 infection continues due to the emergence of multiple transmissible and immune-evasive variants of the SARS-CoV-2 virus. Although various vaccines have been developed and several drugs have been approved for the treatment of COVID-19, the development of new drugs to combat COVID-19 is still necessary. In this work, new 5′-O-ester derivatives of N4-hydroxycytidine based on carboxylic acids were developed and synthesized by Steglich esterification. The antiviral activity of the compounds was assessed in vitro—inhibiting the cytopathic effect of HCoV-229E, and three variants of SARS-CoV-2, on huh-7 and Vero E6 cells. Data have shown that most synthesized derivatives exhibit high activity against coronaviruses. In addition, the relationship between the chemical structure of the compounds and their antiviral effect has been established. The obtained results show that the most active compound was conjugate SN_22 based on 3-methyl phenoxyacetic acid. The results of this study indicate the potential advantage of the chemical strategies used to modify NHC as a promising avenue to be explored in vivo, which could lead to the development of drugs with improved pharmacological properties that potently inhibit SARS-CoV-2. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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15 pages, 2882 KiB  
Article
Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients
by Carmen Gratteri, Francesca Alessandra Ambrosio, Antonio Lupia, Federica Moraca, Bruno Catalanotti, Giosuè Costa, Maria Bellocchi, Luca Carioti, Romina Salpini, Francesca Ceccherini-Silberstein, Simone La Frazia, Vincenzo Malagnino, Loredana Sarmati, Valentina Svicher, Sharon Bryant, Anna Artese and Stefano Alcaro
Pharmaceuticals 2023, 16(8), 1143; https://doi.org/10.3390/ph16081143 - 12 Aug 2023
Viewed by 1422
Abstract
(1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the appearance of resistant mutations could reduce their efficacy. In [...] Read more.
(1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the appearance of resistant mutations could reduce their efficacy. In the present work, we structurally evaluated the impact of RdRp mutations found at baseline in 39 patients treated with remdesivir and associated with a different degree of antiviral response in vivo. (2) Methods: A refined bioinformatics approach was applied to assign SARS-CoV-2 clade and lineage, and to define RdRp mutational profiles. In line with such a method, the same mutations were built and analyzed by combining docking and thermodynamics evaluations with both molecular dynamics and representative pharmacophore models. (3) Results: Clinical studies revealed that patients bearing the most prevalent triple mutant P323L+671S+M899I, which was present in 41% of patients, or the more complex mutational profile P323L+G671S+L838I+D738Y+K91E, which was found with a prevalence of 2.6%, showed a delayed reduced response to remdesivir, as confirmed by the increase in SARS-CoV-2 viral load and by a reduced theoretical binding affinity versus RdRp (ΔGbindWT = −122.70 kcal/mol; ΔGbindP323L+671S+M899I = −84.78 kcal/mol; ΔGbindP323L+G671S+L838I+D738Y+K91E = −96.74 kcal/mol). Combined computational approaches helped to rationalize such clinical observations, offering a mechanistic understanding of the allosteric effects of mutants on the global motions of the viral RNA synthesis machine and in the changes of the interactions patterns of remdesivir during its binding. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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23 pages, 4540 KiB  
Article
Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential
by Arafa Musa, Hamada S. Abulkhair, Ateyatallah Aljuhani, Nadjet Rezki, Mohamed A. Abdelgawad, Khaled Shalaby, Ahmed H. El-Ghorab and Mohamed R. Aouad
Pharmaceuticals 2023, 16(3), 463; https://doi.org/10.3390/ph16030463 - 20 Mar 2023
Cited by 26 | Viewed by 2877
Abstract
COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with [...] Read more.
COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with prominent substituent functionalities were designed and synthesized via a click reaction based on our previous work. The novel compounds were assessed using an in vitro effect on the growth of SARS-CoV-2 virus-infested Vero cells with different compound concentrations: 1 and 10 μM. The data revealed that most of these derivatives showed potent cellular anti-COVID-19 activity and inhibited viral replication by more than 50% with no or weak cytotoxic effect on harboring cells. In addition, in vitro assay employing the SARS-CoV-2-Main protease inhibition assay was done to test the inhibitors’ ability to block the common primary protease of the SARS-CoV-2 virus as a mode of action. The obtained results show that the one non-linker analog 6h and two amide-based linkers 6i and 6q were the most active compounds with IC50 values of 5.08, 3.16, and 7.55 μM, respectively, against the viral protease in comparison to data of the selective antiviral agent GC-376. Molecular modeling studies were done for compound placement within the binding pocket of protease which reveal conserved residues hydrogen bonding and non-hydrogen interactions of 6i analog fragments: triazole scaffold, aryl part, and linker. Moreover, the stability of compounds and their interactions with the target pocket were also studied and analyzed by molecular dynamic simulations. The physicochemical and toxicity profiles were predicted, and the results show that compounds behave as an antiviral activity with low or no cellular or organ toxicity. All research results point to the potential usage of new chemotype potent derivatives as promising leads to be explored in vivo that might open the door to rational drug development of SARS-CoV-2 Main protease potent medicines. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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17 pages, 3262 KiB  
Article
Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches
by Paulo Ricardo Pimenta da Silva Ramos, Melina Mottin, Caroline Sprengel Lima, Letícia R. Assis, Ketllyn Zagato de Oliveira, Nathalya Cristina de Moraes Roso Mesquita, Natasha Marques Cassani, Igor Andrade Santos, Joyce Villa Verde Bastos Borba, Vinícius Alexandre Fiaia Costa, Bruno Junior Neves, Rafael Victorio Carvalho Guido, Glaucius Oliva, Ana Carolina Gomes Jardim, Luis Octávio Regasini and Carolina Horta Andrade
Pharmaceuticals 2022, 15(12), 1493; https://doi.org/10.3390/ph15121493 - 30 Nov 2022
Cited by 9 | Viewed by 2493
Abstract
Although the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural [...] Read more.
Although the past epidemic of Zika virus (ZIKV) resulted in severe neurological consequences for infected infants and adults, there are still no approved drugs to treat ZIKV infection. In this study, we applied computational approaches to screen an in-house database of 77 natural and semi-synthetic compounds against ZIKV NS5 RNA-dependent RNA-polymerase (NS5 RdRp), an essential protein for viral RNA elongation during the replication process. For this purpose, we integrated computational approaches such as binding-site conservation, chemical space analysis and molecular docking. As a result, we prioritized nine virtual hits for experimental evaluation. Enzymatic assays confirmed that pedalitin and quercetin inhibited ZIKV NS5 RdRp with IC50 values of 4.1 and 0.5 µM, respectively. Moreover, pedalitin also displayed antiviral activity on ZIKV infection with an EC50 of 19.28 µM cell-based assays, with low toxicity in Vero cells (CC50 = 83.66 µM) and selectivity index of 4.34. These results demonstrate the potential of the natural compounds pedalitin and quercetin as candidates for structural optimization studies towards the discovery of new anti-ZIKV drug candidates. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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9 pages, 1956 KiB  
Article
Synthesis of Novel N4-Hydrocytidine Analogs as Potential Anti-SARS-CoV-2 Agents
by Franck Amblard, Julia C. LeCher, Ramyani De, Shu Ling Goh, Chengwei Li, Mahesh Kasthuri, Nicolas Biteau, Longhu Zhou, Zahira Tber, Jessica Downs-Bowen, Keivan Zandi and Raymond F. Schinazi
Pharmaceuticals 2022, 15(9), 1144; https://doi.org/10.3390/ph15091144 - 14 Sep 2022
Cited by 4 | Viewed by 2237
Abstract
Coronavirus disease 2019 (COVID-19) is an emerging global pandemic with severe morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molnupiravir, an ester prodrug form of N4-hydroxycytidine (NHC), was recently emergency-use approved for the treatment of early [...] Read more.
Coronavirus disease 2019 (COVID-19) is an emerging global pandemic with severe morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molnupiravir, an ester prodrug form of N4-hydroxycytidine (NHC), was recently emergency-use approved for the treatment of early SARS-CoV-2 infections. Herein, we report the synthesis and evaluation of a series of novel NHC analogs. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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18 pages, 9713 KiB  
Article
Fludarabine, a Potential DNA-Dependent RNA Polymerase Inhibitor, as a Prospective Drug against Monkeypox Virus: A Computational Approach
by Hisham N. Altayb
Pharmaceuticals 2022, 15(9), 1129; https://doi.org/10.3390/ph15091129 - 9 Sep 2022
Cited by 27 | Viewed by 4140
Abstract
Monkeypox is a zoonotic contagious disease that has recently re-emerged in different countries worldwide. Due to the lack of an effective treatment that eliminates the virus, there is an urgent need to find effective drugs to stop the spread of the multi-country outbreak. [...] Read more.
Monkeypox is a zoonotic contagious disease that has recently re-emerged in different countries worldwide. Due to the lack of an effective treatment that eliminates the virus, there is an urgent need to find effective drugs to stop the spread of the multi-country outbreak. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Monkeypox virus (MPXV). Three MPXV proteins were targeted in this study due to their essential role in viral replication (a DNA-Dependent RNA Polymerase subunit (A6R)), a protein involved in cell entry (D8L), and a protein catalyzing the envelopment of intracellular mature virus particles (F13L). We virtually screened a library of 1615 FDA-approved compounds, utilizing different in-silico approaches including computational modeling, molecular docking, molecular dynamic (MD) simulation, and MM-GBSA. The compound Fludarabine was found to have the best docking score (−7.53 kcal/mol) in relation to the MPXV A6R protein. Additionally, Fludarabine showed in-silico activity on the D8L and F13L proteins. During the whole period of the 100 ns MD simulation, the complex of A6R and Fludarabine exhibited the best stability. This stability was reflected in a good score of MM-GBSA, with an average value of −44.62 kcal/mole in a range between −53.26 and −35.49 and a low value of standard deviation (3.76). Furthermore, Fludarabine blocked efficiently the Asn175 residue which has an important role in the attachment of the virus to a host cell. The results of this study recommend more in vitro studies on this compound, as a starting point to develop a novel treatment against MPXV. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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Review

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37 pages, 11458 KiB  
Review
Small Molecule Drugs Targeting Viral Polymerases
by Deborah Palazzotti, Martina Sguilla, Giuseppe Manfroni, Violetta Cecchetti, Andrea Astolfi and Maria Letizia Barreca
Pharmaceuticals 2024, 17(5), 661; https://doi.org/10.3390/ph17050661 - 20 May 2024
Cited by 1 | Viewed by 3195
Abstract
Small molecules that specifically target viral polymerases—crucial enzymes governing viral genome transcription and replication—play a pivotal role in combating viral infections. Presently, approved polymerase inhibitors cover nine human viruses, spanning both DNA and RNA viruses. This review provides a comprehensive analysis of these [...] Read more.
Small molecules that specifically target viral polymerases—crucial enzymes governing viral genome transcription and replication—play a pivotal role in combating viral infections. Presently, approved polymerase inhibitors cover nine human viruses, spanning both DNA and RNA viruses. This review provides a comprehensive analysis of these licensed drugs, encompassing nucleoside/nucleotide inhibitors (NIs), non-nucleoside inhibitors (NNIs), and mutagenic agents. For each compound, we describe the specific targeted virus and related polymerase enzyme, the mechanism of action, and the relevant bioactivity data. This wealth of information serves as a valuable resource for researchers actively engaged in antiviral drug discovery efforts, offering a complete overview of established strategies as well as insights for shaping the development of next-generation antiviral therapeutics. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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