Small Molecule Antivirals

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 8148

Special Issue Editors

Surgical and Experimental Medical Sciences, Università degli Studi di Sassari, Sassari, Italy
Interests: antiviral drug discovery
Special Issues, Collections and Topics in MDPI journals
Department of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23A, 07100 Sassari, Italy
Interests: medicinal chemistry; drug design; anticancer drugs; antiviral; VEGFR-2; natural compounds; antioxidants; fragment-based drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Viruses are obligate intracellular parasites that lack the assets for self-reproduction, so they take over host cell’s metabolic pathways to complete a viral life cycle. Together, they encode specific viral proteins that are vital for producing progeny virions. The inhibition of both viral or host proteins involved in the viral replication is challenging; the obtained compounds may be toxic or lack selectivity.

For this reason, the antiviral research of potent and selective antiviral drugs is still critical, as the recent coronavirus pandemic pointed out.

This Special Issue aims to collect original research articles, reviews, or letters focused on the identification of synthetic, semi-synthetic, or naturally derived molecules related with antiviral activity, as well as the study of mechanisms of action and mechanisms of drug resistance. Furthermore, identification of new antiviral targets, or potential ones, are more than welcome.

Dr. Antonio Carta
Dr. Roberta Ibba
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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

  • antiviral drug discovery
  • synthetic antivirals
  • natural antiviral compounds
  • antiviral drug resistance
  • antiviral targets

Published Papers (4 papers)

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Research

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17 pages, 2841 KiB  
Article
Evaluation of Histone Demethylase Inhibitor ML324 and Acyclovir against Cyprinid herpesvirus 3 Infection
by Shelby Matsuoka, Gloria Petri, Kristen Larson, Alexandra Behnke, Xisheng Wang, Muhui Peng, Sean Spagnoli, Christiane Lohr, Ruth Milston-Clements, Konstantin Divilov and Ling Jin
Viruses 2023, 15(1), 163; https://doi.org/10.3390/v15010163 - 05 Jan 2023
Viewed by 1373
Abstract
Cyprinid herpesvirus 3 (CyHV-3) can cause severe disease in koi and common carp (Cyprinus carpio). Currently, no effective treatment is available against CyHV-3 infection in koi. Both LSD1 and JMJD2 are histone demethylases (HD) and are critical for immediate-early (IE) gene [...] Read more.
Cyprinid herpesvirus 3 (CyHV-3) can cause severe disease in koi and common carp (Cyprinus carpio). Currently, no effective treatment is available against CyHV-3 infection in koi. Both LSD1 and JMJD2 are histone demethylases (HD) and are critical for immediate-early (IE) gene activation essential for lytic herpesvirus replication. OG-L002 and ML324 are newly discovered specific inhibitors of LSD1 and JMJD2, respectively. Here, HD inhibitors were compared with acyclovir (ACV) against CyHV-3 infection in vitro and in vivo. ML324, at 20–50 µM, can completely block ~1 × 103 PFU CyHV-3 replication in vitro, while OG-L002 at 20 µM and 50 µM can produce 96% and 98% inhibition, respectively. Only about 94% inhibition of ~1 × 103 PFU CyHV-3 replication was observed in cells treated with ACV at 50 µM. As expected, CyHV-3 IE gene transcription of ORF139 and ORF155 was blocked within 72 h post-infection (hpi) in the presence of 20 µM ML324. No detectable cytotoxicity was observed in KF-1 or CCB cells treated for 24 h with 1 to 50 µM ML324. A significant reduction of CyHV-3 replication was observed in ~6-month-old infected koi treated with 20 µM ML324 in an immersion bath for 3–4 h at 1-, 3-, and 5-days post-infection compared to the control and ACV treatments. Under heat stress, 50–70% of 3–4-month-old koi survived CyHV-3 infection when they were treated daily with 20 µM ML324 in an immersion bath for 3–4 h within the first 5 d post-infection (dpi), compared to 11–19% and 22–27% of koi in the control and ACV treatments, respectively. Our study demonstrates that ML324 has the potential to be used against CyHV-3 infection in koi. Full article
(This article belongs to the Special Issue Small Molecule Antivirals)
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17 pages, 5097 KiB  
Article
Inhibitors of Deubiquitinating Enzymes Interfere with the SARS-CoV-2 Papain-like Protease and Block Virus Replication In Vitro
by Maximilian Große, Christian Setz, Pia Rauch, Janina Auth, Martina Morokutti-Kurz, Vladimir Temchura and Ulrich Schubert
Viruses 2022, 14(7), 1404; https://doi.org/10.3390/v14071404 - 27 Jun 2022
Cited by 7 | Viewed by 2062
Abstract
The ubiquitin proteasome system (UPS), particularly its deubiquitinating enzymes (DUBs), play a key role in the replication cycle of coronaviruses. The SARS-CoV-2 papain-like protease (Plpro) is known to process the viral polyproteins to form the replicase transcriptase complex and to counteract the host [...] Read more.
The ubiquitin proteasome system (UPS), particularly its deubiquitinating enzymes (DUBs), play a key role in the replication cycle of coronaviruses. The SARS-CoV-2 papain-like protease (Plpro) is known to process the viral polyproteins to form the replicase transcriptase complex and to counteract the host viral response. Recently, it was shown that this viral protease can also act as a deubiquitinating enzyme. In this study, we demonstrate that certain DUB-Inhibitors (DIs) interfere with SARS-CoV-2 replication. The DIs PR-619 and HBX41108 restrict SARS-CoV-2 in both Vero B4 and human Calu-3 lung cells where cells were infected with a Multiplicity of Infection (MOI) of 0.02. An in vitro protease assay using recombinant Plpro and Amido-4-methylcoumarin (AMC)-conjugated substrate revealed that PR-619 and HBX41108 are able to block the protease at concentrations where the interventions restricted virus replication. In contrast, DIs that do not inhibit Plpro had no influence on virus replication, which indicated that the protease might be at least one major target. Future vertical studies that would gain more insights into the mechanisms of how DUBs effect the replication of SARS-CoV-2 will further validate them as a potential therapeutic target. Full article
(This article belongs to the Special Issue Small Molecule Antivirals)
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21 pages, 4829 KiB  
Article
Benzimidazole-2-Phenyl-Carboxamides as Dual-Target Inhibitors of BVDV Entry and Replication
by Roberta Ibba, Federico Riu, Ilenia Delogu, Ilenia Lupinu, Gavino Carboni, Roberta Loddo, Sandra Piras and Antonio Carta
Viruses 2022, 14(6), 1300; https://doi.org/10.3390/v14061300 - 14 Jun 2022
Cited by 4 | Viewed by 2175
Abstract
Bovine viral diarrhea virus (BVDV), also known as Pestivirus A, causes severe infection mostly in cattle, but also in pigs, sheep and goats, causing huge economical losses on agricultural farms every year. The infections are actually controlled by isolation of persistently infected animals [...] Read more.
Bovine viral diarrhea virus (BVDV), also known as Pestivirus A, causes severe infection mostly in cattle, but also in pigs, sheep and goats, causing huge economical losses on agricultural farms every year. The infections are actually controlled by isolation of persistently infected animals and vaccination, but no antivirals are currently available to control the spread of BVDV on farms. BVDV binds the host cell using envelope protein E2, which has only recently been targeted in the research of a potent and efficient antiviral. In contrast, RdRp has been successfully inhibited by several classes of compounds in the last few decades. As a part of an enduring antiviral research agenda, we designed a new series of derivatives that emerged from an isosteric substitution of the main scaffold in previously reported anti-BVDV compounds. Here, the new compounds were characterized and tested, where several turned out to be potent and selectively active against BVDV. The mechanism of action was thoroughly studied using a time-of-drug-addition assay and the results were validated using docking simulations. Full article
(This article belongs to the Special Issue Small Molecule Antivirals)
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Review

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19 pages, 4149 KiB  
Review
Developments in Exploring Fungal Secondary Metabolites as Antiviral Compounds and Advances in HIV-1 Inhibitor Screening Assays
by Bruce Nzimande, John P. Makhwitine, Nompumelelo P. Mkhwanazi and Sizwe I. Ndlovu
Viruses 2023, 15(5), 1039; https://doi.org/10.3390/v15051039 - 23 Apr 2023
Cited by 2 | Viewed by 1987
Abstract
The emergence of drug-resistant Human Immunodeficiency Virus-1 strains against anti-HIV therapies in the clinical pipeline, and the persistence of HIV in cellular reservoirs remains a significant concern. Therefore, there is a continuous need to discover and develop new, safer, and effective drugs targeting [...] Read more.
The emergence of drug-resistant Human Immunodeficiency Virus-1 strains against anti-HIV therapies in the clinical pipeline, and the persistence of HIV in cellular reservoirs remains a significant concern. Therefore, there is a continuous need to discover and develop new, safer, and effective drugs targeting novel sites to combat HIV-1. The fungal species are gaining increasing attention as alternative sources of anti-HIV compounds or immunomodulators that can escape the current barriers to cure. Despite the potential of the fungal kingdom as a source for diverse chemistries that can yield novel HIV therapies, there are few comprehensive reports on the progress made thus far in the search for fungal species with the capacity to produce anti-HIV compounds. This review provides insights into the recent research developments on natural products produced by fungal species, particularly fungal endophytes exhibiting immunomodulatory or anti-HIV activities. In this study, we first explore currently existing therapies for various HIV-1 target sites. Then we assess the various activity assays developed for gauging antiviral activity production from microbial sources since they are crucial in the early screening phases for discovering novel anti-HIV compounds. Finally, we explore fungal secondary metabolites compounds that have been characterized at the structural level and demonstrate their potential as inhibitors of various HIV-1 target sites. Full article
(This article belongs to the Special Issue Small Molecule Antivirals)
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