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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 21885

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Dr. Natalie Borg

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Head, Immunity and Immune Evasion Lab, School of Health and Biomedical Sciences, RMIT University, Bundoora 3083, Australia
Interests: antiviral immunity; infection; nucleocytoplasmic transport; immune evasion host-pathogen interactions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Only around 3% of known human viral pathogens are able to be treated with Food and Drug Administration (FDA)‐approved antivirals, and given these are mostly virus-targeted, drug resistance jeopardizes their efficacy. Further, the COVID-19 pandemic has highlighted major shortfalls and a lack of foresight in drug development against newly emerging viruses. This is why our ‘best’ option is to repurpose familiar drugs to treat COVID-19 patients. We urgently require new strategies to prevent and treat existing/emerging infections if we are to circumvent future significant health and economic global crises. This Special issue aims to give an overview of the most recent advances in antiviral drug development and new therapeutic targeting strategies.

Potential topics include but are not limited to:

Antiviral drugs;
Mechanisms of action;
Perspectives for antiviral drug development;
Future perspectives for newly emerging viruses;
Host-targeted therapies;
Identification of antiviral targets.

Dr. Natalie Borg
Guest Editor

Manuscript Submission Information

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Keywords

antiviral
drug
drug resistance
virus

Published Papers (11 papers)

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Research

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17 pages, 3838 KiB

Open AccessArticle

Antiviral Activity of Flavonoids from Geopropolis of the Brazilian Jandaira Bee against Zika and Dengue Viruses

by Poliana Gomes da Silva, Elton José Ferreira Chaves, Tania Maria Sarmento Silva, Gerd Bruno Rocha, Willyenne Marília Dantas, Ronaldo Nascimento de Oliveira and Lindomar José Pena

Pharmaceutics 2023, 15(10), 2494; https://doi.org/10.3390/pharmaceutics15102494 - 19 Oct 2023

Cited by 2 | Viewed by 1194

Abstract

Arthropod-borne viruses within the Flaviviridae family such as Zika (ZIKV) and dengue (DENV) are responsible for major outbreaks in tropical countries, and there are no specific treatments against them. Naringenin and 7-O-methyl naringenin are flavonoids that can be extracted from geopropolis, a natural material that the Brazilian Jandaira stingless bee (Melipona subnitida Ducke) produces to protect its nest. Here, these flavonoids were tested against ZIKV and DENV using Vero cells as a cellular model to perform a cytotoxicity assay and to define the effective concentrations of TCID₅₀ as the readout method. The results demonstrated the antiviral activity of the compounds against both viruses upon the treatment of infected cells. The tested flavonoids had antiviral activity comparable with 6-methylmercaptopurine riboside (6-MMPr), used here as a positive control. In addition, to identify the possible action mechanism of the antiviral candidates, we carried out a docking analysis followed by a molecular dynamics simulation to elucidate naringenin and 7-O-methyl naringenin binding sites to each virus. Altogether, these results demonstrate that both flavonoids have potent antiviral effects against both viruses and warrant further in vivo trials. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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17 pages, 1658 KiB

Open AccessArticle

Increased In Vivo Exposure of N-(4-Hydroxyphenyl) Retinamide (4-HPR) to Achieve Plasma Concentrations Effective against Dengue Virus

by Alexander J. Martin, David M. Shackleford, Susan A. Charman, Kylie M. Wagstaff, Christopher J. H. Porter and David A. Jans

Pharmaceutics 2023, 15(7), 1974; https://doi.org/10.3390/pharmaceutics15071974 - 18 Jul 2023

Viewed by 1107

Abstract

N-(4-hydroxyphenyl) retinamide (4-HPR, or fenretinide) has promising in vitro and in vivo antiviral activity against a range of flaviviruses and an established safety record, but there are challenges to its clinical use. This study evaluated the in vivo exposure profile of a 4-HPR dosage regime previously shown to be effective in a mouse model of severe dengue virus (DENV) infection, comparing it to an existing formulation for human clinical use for other indications and developed/characterised self-emulsifying lipid-based formulations of 4-HPR to enhance 4-HPR in vivo exposure. Pharmacokinetic (PK) analysis comprising single-dose oral and IV plasma concentration-time profiles was performed in mice; equilibrium solubility testing of 4-HPR in a range of lipids, surfactants and cosolvents was used to inform formulation approaches, with lead formulation candidates digested in vitro to analyse solubilisation/precipitation prior to in vivo testing. PK analysis suggested that effective plasma concentrations could be achieved with the clinical formulation, while novel lipid-based formulations achieved > 3-fold improvement. Additionally, 4-HPR exposure was found to be limited by both solubility and first-pass intestinal elimination but could be improved through inhibition of cytochrome P450 (CYP) metabolism. Simulated exposure profiles suggest that a b.i.d dosage regime is likely to maintain 4-HPR above the minimum effective plasma concentration for anti-DENV activity using the clinical formulation, with new formulations/CYP inhibition viable options to increase exposure in the future. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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24 pages, 5363 KiB

Open AccessArticle

Montelukast and Telmisartan as Inhibitors of SARS-CoV-2 Omicron Variant

by Nirmitee Mulgaonkar, Haoqi Wang, Junrui Zhang, Christopher M. Roundy, Wendy Tang, Sankar Prasad Chaki, Alex Pauvolid-Corrêa, Gabriel L. Hamer and Sandun Fernando

Pharmaceutics 2023, 15(7), 1891; https://doi.org/10.3390/pharmaceutics15071891 - 5 Jul 2023

Cited by 3 | Viewed by 1698

Abstract

Earlier studies with montelukast (M) and telmisartan (T) have revealed their potential antiviral properties against SARS-CoV-2 wild-type (WT) but have not assessed their efficacy against emerging Variants of Concern (VOCs) such as Omicron. Our research fills this gap by investigating these drugs’ impact on VOCs, a topic that current scientific literature has largely overlooked. We employed computational methodologies, including molecular mechanics and machine learning tools, to identify drugs that could potentially disrupt the SARS-CoV-2 spike RBD-ACE2 protein interaction. This led to the identification of two FDA-approved small molecule drugs, M and T, conventionally used for treating asthma and hypertension, respectively. Our study presents an additional potential use for these drugs as antivirals. Our results show that both M and T can inhibit not only the WT SARS-CoV-2 but also, in the case of M, the Omicron variant, without reaching cytotoxic concentrations. This novel finding fills an existing gap in the literature and introduces the possibility of repurposing these drugs for SARS-CoV-2 VOCs, an essential step in responding to the evolving global pandemic. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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11 pages, 4227 KiB

Open AccessArticle

Urtica dioica Agglutinin Prevents Rabies Virus Infection in a Muscle Explant Model

by Xinyu Wang, Lisanne Terrie, Guanghui Wu, Els J. M. Van Damme, Lieven Thorrez, Anthony R. Fooks, Ashley C. Banyard, Dirk Jochmans and Johan Neyts

Pharmaceutics 2023, 15(5), 1353; https://doi.org/10.3390/pharmaceutics15051353 - 28 Apr 2023

Cited by 2 | Viewed by 1631

Abstract

Infection with the rabies virus (RABV) results in a 100% lethal neurological disease once symptoms develop. Post-exposure prophylaxis (PEP) consists of a combination of vaccination and anti-rabies immunoglobulins (RIGs); it is 100% effective if administered early after exposure. Because of its limited availability, alternatives for RIGs are needed. To that end, we evaluated a panel of 33 different lectins for their effect on RABV infection in cell culture. Several lectins, with either mannose or GlcNAc specificity, elicited anti-RABV activity, of which the GlcNAc-specific Urtica dioica agglutinin (UDA) was selected for further studies. UDA was found to prevent the entry of the virus into the host cell. To further assess the potential of UDA, a physiologically relevant RABV infection muscle explant model was developed. Strips of dissected swine skeletal muscle that were kept in a culture medium could be productively infected with the RABV. When the infection of the muscle strips was carried out in the presence of UDA, RABV replication was completely prevented. Thus, we developed a physiologically relevant RABV muscle infection model. UDA (i) may serve as a reference for further studies and (ii) holds promise as a cheap and simple-to-produce alternative for RIGs in PEP. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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14 pages, 6350 KiB

Open AccessArticle

Antiviral Mechanisms of N-Phenyl Benzamides on Coxsackie Virus A9

by Mira Laajala, Kerttu Kalander, Sara Consalvi, Olivier Sheik Amamuddy, Özlem Tastan Bishop, Mariangela Biava, Giovanna Poce and Varpu Marjomäki

Pharmaceutics 2023, 15(3), 1028; https://doi.org/10.3390/pharmaceutics15031028 - 22 Mar 2023

Cited by 2 | Viewed by 1814

Abstract

Enteroviruses are one of the most abundant groups of viruses infecting humans, and yet there are no approved antivirals against them. To find effective antiviral compounds against enterovirus B group viruses, an in-house chemical library was screened. The most effective compounds against Coxsackieviruses B3 (CVB3) and A9 (CVA9) were CL212 and CL213, two N-phenyl benzamides. Both compounds were more effective against CVA9 and CL213 gave a better EC₅₀ value of 1 µM with high a specificity index of 140. Both drugs were most effective when incubated directly with viruses suggesting that they mainly bound to the virions. A real-time uncoating assay showed that the compounds stabilized the virions and radioactive sucrose gradient as well as TEM confirmed that the viruses stayed intact. A docking assay, taking into account larger areas around the 2-and 3-fold axes of CVA9 and CVB3, suggested that the hydrophobic pocket gives the strongest binding to CVA9 but revealed another binding site around the 3-fold axis which could contribute to the binding of the compounds. Together, our data support a direct antiviral mechanism against the virus capsid and suggest that the compounds bind to the hydrophobic pocket and 3-fold axis area resulting in the stabilization of the virion. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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13 pages, 1913 KiB

Open AccessArticle

Antiviral Mechanism of Virucidal Sialic Acid Modified Cyclodextrin

by Yong Zhu, Andrey A. Sysoev, Paulo H. Jacob Silva, Marine Batista and Francesco Stellacci

Pharmaceutics 2023, 15(2), 582; https://doi.org/10.3390/pharmaceutics15020582 - 9 Feb 2023

Cited by 6 | Viewed by 2498

Abstract

We have reported that CD-6′SLN [6-sialyllactosamine (6′SLN)-modified β-cyclodextrin (CD)] can be a potential anti-influenza drug because it irreversibly deactivates virions. Indeed, in vivo, CD-6′SLN improved mice survival in an H1N1 infection model even when administered 24 h post-infection. Although CD-6′SLN was designed to target the viral envelope protein hemagglutinin (HA), a natural receptor of 6′SLN, it remains unclear whether other targets exist. In this study, we confirm that CD-6′SLN inhibits the influenza virus through an extracellular mechanism by interacting with HA, but not with neuraminidase (NA), despite the latter also having a binding pocket for the sialyl group. We find that CD-6′SLN interacts with the viral envelope as it elicits the release of a fluorophore embedded in the membrane. Two similar compounds were designed to test separately the effect of 6′SLN and of the undecyl moiety that links the CD to 6′SLN. Neither showed any interaction with the membrane nor the irreversible viral inhibition (virucidal), confirming that both components are essential to membrane interaction and virucidal action. Unlike similar antiviral cyclodextrins developed against other viruses, CD-6′SLN was not able to decapsulate viral RNA. Our findings support that combining viral protein-specific epitopes with hydrophobic linkers provides a strategy for developing antiviral drugs with a virucidal mechanism. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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25 pages, 4383 KiB

Open AccessArticle

Chemokine Receptors—Structure-Based Virtual Screening Assisted by Machine Learning

by Paulina Dragan, Matthew Merski, Szymon Wiśniewski, Swapnil Ganesh Sanmukh and Dorota Latek

Pharmaceutics 2023, 15(2), 516; https://doi.org/10.3390/pharmaceutics15020516 - 3 Feb 2023

Cited by 5 | Viewed by 2105

Abstract

Chemokines modulate the immune response by regulating the migration of immune cells. They are also known to participate in such processes as cell–cell adhesion, allograft rejection, and angiogenesis. Chemokines interact with two different subfamilies of G protein-coupled receptors: conventional chemokine receptors and atypical chemokine receptors. Here, we focused on the former one which has been linked to many inflammatory diseases, including: multiple sclerosis, asthma, nephritis, and rheumatoid arthritis. Available crystal and cryo-EM structures and homology models of six chemokine receptors (CCR1 to CCR6) were described and tested in terms of their usefulness in structure-based drug design. As a result of structure-based virtual screening for CCR2 and CCR3, several new active compounds were proposed. Known inhibitors of CCR1 to CCR6, acquired from ChEMBL, were used as training sets for two machine learning algorithms in ligand-based drug design. Performance of LightGBM was compared with a sequential Keras/TensorFlow model of neural network for these diverse datasets. A combination of structure-based virtual screening with machine learning allowed to propose several active ligands for CCR2 and CCR3 with two distinct compounds predicted as CCR3 actives by all three tested methods: Glide, Keras/TensorFlow NN, and LightGBM. In addition, the performance of these three methods in the prediction of the CCR2/CCR3 receptor subtype selectivity was assessed. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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14 pages, 1336 KiB

Open AccessArticle

The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types

by Friedrich Hahn, Christina Wangen, Sigrun Häge, Lars Herrmann, Alexandra Herrmann, Svetlana B. Tsogoeva and Manfred Marschall

Pharmaceutics 2023, 15(1), 115; https://doi.org/10.3390/pharmaceutics15010115 - 29 Dec 2022

Cited by 1 | Viewed by 2545

Abstract

Starting in 2019, the spread of respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated pandemic of the corona virus disease (COVID-19) has led to enormous efforts in the development of medical countermeasures. Although innovative vaccines have scaled back the number of severe COVID cases, the emergence of the omicron variant (B.1.1.529) illustrates how vaccine development struggles to keep pace with viral evolution. On the other hand, while the recently approved antiviral drugs remdesivir, molnupiravir, and Paxlovid are considered as broadly acting anti-coronavirus therapeutics, only molnupiravir and Paxlovid are orally available and none of these drugs are recommended for prophylactic use. Thus, so far unexploited small molecules, targeting strategies, and antiviral mechanisms are urgently needed to address issues in the current pandemic and in putative future outbreaks of newly emerging variants of concern. Recently, we and others have described the anti-infective potential and particularly the pronounced antiviral activity of artesunate and related compounds of the trioxane/sesquiterpene class. In particular, the trimeric derivative TF27 demonstrated strong anti-cytomegalovirus activity at nanomolar concentrations in vitro as well as in vivo efficacy after oral administration in therapeutic and even prophylactic treatment settings. Here, we extended this analysis by evaluating TF27 for its anti-SARS-CoV-2 potential. Our main findings are as follows: (i) compound TF27 exerted strong anti-SARS-CoV-2 activity in vitro (EC₅₀ = 0.46 ± 0.20 µM), (ii) antiviral activity was clearly distinct from the induction of cytotoxicity, (iii) pretreatment with TF27 prevented virus replication in cultured cells, (iv) antiviral activity has likewise been demonstrated in Calu-3 human lung and Caco-2 human colon cells infected with wild-type, delta, or omicron SARS-CoV-2, respectively, and (v) analysis of TF27 combination treatments has revealed synergistic interaction with GC376, but antagonistic interaction with EIDD-1931. Combined, the data demonstrated the pronounced anti-SARS-CoV-2 activity of TF27 and thus highlight the potential of trioxane compounds for further pharmacologic development towards improved options for COVID-specific medication. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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20 pages, 2095 KiB

Open AccessArticle

Synthesis of Novel 1,3,4-Oxadiazole-Derived α-Aminophosphonates/α-Aminophosphonic Acids and Evaluation of Their In Vitro Antiviral Activity against the Avian Coronavirus Infectious Bronchitis Virus

by Shaima Hkiri, Marwa Mekni-Toujani, Elvan Üstün, Karim Hosni, Abdeljelil Ghram, Soufiane Touil, Ali Samarat and David Sémeril

Pharmaceutics 2023, 15(1), 114; https://doi.org/10.3390/pharmaceutics15010114 - 29 Dec 2022

Cited by 5 | Viewed by 1768

Abstract

An efficient and simple approach has been developed for the synthesis of eight dialkyl/aryl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(aryl)methyl]phosphonates through the Pudovik-type reaction of dialkyl/arylphosphite with imines, obtained from 5-phenyl-1,3,4-oxadiazol-2-amine and aromatic aldehydes, under microwave irradiation. Five of them were hydrolyzed to lead to the corresponding phosphonic acids. Selected synthesized compounds were screened for their in vitro antiviral activity against the avian bronchitis virus (IBV). In the MTT cytotoxicity assay, the dose-response curve showed that all test compounds were safe in the range concentration of 540–1599 µM. The direct contact of novel synthesized compounds with IBV showed that the diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethoxyphenyl)methyl]phosphonate (5f) (at 33 µM) and the [(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethylphenyl)methyl] phosphonic acid (6a) (at 1.23 µM) strongly inhibited the IBV infectivity, indicating their high virucidal activity. However, virus titers from IBV-infected Vero cells remained unchanged in response to treatment with the lowest non-cytotoxic concentrations of synthesized compounds suggesting their incapacity to inhibit the virus replication inside the host cell. Lack of antiviral activity might presumably be ascribed to their polarity that hampers their diffusion across the lipophilic cytoplasmic membrane. Therefore, the interactions of 5f and 6a were analyzed against the main coronavirus protease, papain-like protease, and nucleocapsid protein by molecular docking methods. Nevertheless, the novel 1,3,4-oxadiazole-based α-aminophosphonic acids and α-amino-phosphonates hold potential for developing new hygienic virucidal products for domestic, chemical, and medical uses. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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Review

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17 pages, 636 KiB

Open AccessReview

Modulating Immune Response in Viral Infection for Quantitative Forecasts of Drug Efficacy

by Bárbara Costa and Nuno Vale

Pharmaceutics 2023, 15(1), 167; https://doi.org/10.3390/pharmaceutics15010167 - 3 Jan 2023

Viewed by 1526

Abstract

The antiretroviral drug, the total level of viral production, and the effectiveness of immune responses are the main topics of this review because they are all dynamically interrelated. Immunological and viral processes interact in extremely complex and non-linear ways. For reliable analysis and quantitative forecasts that may be used to follow the immune system and create a disease profile for each patient, mathematical models are helpful in characterizing these non-linear interactions. To increase our ability to treat patients and identify individual differences in disease development, immune response profiling might be useful. Identifying which patients are moving from mild to severe disease would be more beneficial using immune system parameters. Prioritize treatments based on their inability to control the immune response and prevent T cell exhaustion. To increase treatment efficacy and spur additional research in this field, this review intends to provide examples of the effects of modelling immune response in viral infections, as well as the impact of pharmaceuticals on immune response. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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20 pages, 3211 KiB

Open AccessReview

Flavonoids as Potential Antiviral Agents for Porcine Viruses

by Xinwei Zhang, Si Chen, Xue Li, Liying Zhang and Linzhu Ren

Pharmaceutics 2022, 14(9), 1793; https://doi.org/10.3390/pharmaceutics14091793 - 26 Aug 2022

Cited by 7 | Viewed by 2474

Abstract

Flavonoids are types of natural substances with phenolic structures isolated from a variety of plants. Flavonoids have antioxidant, anti-inflammatory, anticancer, and antiviral activities. Although most of the research or applications of flavonoids are focused on human diseases, flavonoids also show potential applicability against porcine virus infection. This review focuses on the recent progress in antiviral mechanisms of potential flavonoids against the most common porcine viruses. The mechanism discussed in this paper may provide a theoretical basis for drug screening and application of natural flavonoid compounds and flavonoid-containing herbs to control porcine virus infection and guide the research and development of pig feed additives. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral Drug Development)

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