Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.3
3.8
Journals
Viruses
Special Issues
Viral Replication Inhibitors
share announcement

Viral Replication Inhibitors

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 (30 November 2024) | Viewed by 9020

Special Issue Editors

Dr. Danielle Poulin Porter

E-Mail Website
Guest Editor
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
Interests: virology; microbiology; molecular biology; biotechnology
Dr. Meghan Vermillion

E-Mail Website
Guest Editor
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
Interests: models of infectious disease; respiratory physiology; mucosal immunology; reproductive biology

Special Issue Information

Dear Colleagues,

Many of the most effective antiviral agents currently approved for the treatment of human viral infections, including those caused by human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), hepatitis delta virus (HDV), herpesviruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Ebola virus and influenza virus, act by successfully disrupting essential steps of the viral replication cycle. Viral replication inhibitors frequently target viral enzymes required for replication such as polymerases, proteases, integrases and reverse transcriptases. Other critical stages of the virus life cycle, such as viral attachment and entry, are also potential targets for inhibition. While tremendous progress has been made in the past several decades in developing viral replication inhibitors for clinical use, there are still many significant human viral diseases for which no treatment is currently available, including infections caused by measles virus, respiratory syncytial virus (RSV), rhinovirus, poliovirus, norovirus, yellow fever virus and dengue virus.

We are pleased to invite you to contribute a manuscript to this Special Issue of Viruses on viral replication inhibitors. Here, we aim to address recent advances in the development and application of replication inhibitors of human pathogenic viruses. We welcome the submission of original research, reviews, and mini-reviews covering, but not limited to, the following topics: mechanism of action (MOA) studies, viral drug resistance, novel inhibitors, expanded applications of existing inhibitors, animal efficacy data, clinical data and case studies.

We look forward to receiving your contributions.

Dr. Danielle Poulin Porter
Dr. Meghan Vermillion
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. Viruses 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 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 drugs
  • integrase inhibitors
  • mechanism of action
  • reverse transcriptase inhibitors
  • protease inhibitors
  • polymerase inhibitors
  • entry inhibitors
  • viral infectious disease
  • small-molecule inhibitors
  • antibodies
  • viral resistance

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (6 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

14 pages, 2816 KiB  
Article
The Combination of GS-441524 (Remdesivir) and Ribavirin Results in a Potent Antiviral Effect Against Human Parainfluenza Virus 3 Infection in Human Airway Epithelial Cell Cultures and in a Mouse Infection Model
by Yuxia Lin, Birgit Weynand, Xin Zhang, Manon Laporte, Dirk Jochmans and Johan Neyts
Viruses 2025, 17(2), 172; https://doi.org/10.3390/v17020172 - 26 Jan 2025
Viewed by 542
Abstract
Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory diseases, particularly in young children, the elderly and immunocompromised. There are no approved antiviral drugs against this virus. We report that the combination of ribavirin with either remdesivir or its parent nucleoside GS-441524 [...] Read more.
Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory diseases, particularly in young children, the elderly and immunocompromised. There are no approved antiviral drugs against this virus. We report that the combination of ribavirin with either remdesivir or its parent nucleoside GS-441524 results in a pronounced antiviral effect against HPIV-3 in LLC-MK2 cells and in human airway epithelial cells grown at the air–liquid interface. In AG129 mice intranasally inoculated with HPIV-3, the combined treatment with ribavirin and GS-441524 decreased infectious viral lung titers by >2.5 log10 to undetectable levels in 4 out of 11 mice and by 1.6 log10 in the remaining 7 mice as compared with the vehicle. The lungs of all mice that received the combined treatment appeared histologically normal or virtually normal, whereas 8 of 11 vehicle-treated mice presented with bronchopneumonia. By contrast, ribavirin alone did not result in a reduction in infectious viral lung titers; GS-441524 alone reduced infectious viral lung titers by 1.2 log10. Moreover, several mice in the single-treatment groups exhibited severe lung pathology. These findings may warrant exploring this combination in patients with severe HPIV-3 infections and possibly also against infections with other viruses that are susceptible in vitro to these two drugs. Full article
(This article belongs to the Special Issue Viral Replication Inhibitors)
►▼ Show Figures

Figure 1

25 pages, 6527 KiB  
Article
Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals
by Ali Zahedi Amiri, Choudhary Ahmed, Subha Dahal, Filomena Grosso, Haomin Leng, Peter Stoilov, Maria Mangos, Johanne Toutant, Lulzim Shkreta, Liliana Attisano, Benoit Chabot, Martha Brown, Mario Huesca and Alan Cochrane
Viruses 2025, 17(1), 54; https://doi.org/10.3390/v17010054 - 31 Dec 2024
Viewed by 975
Abstract
Treatment options for viral infections are limited and viruses have proven adept at evolving resistance to many existing therapies, highlighting a significant vulnerability in our defenses. In response to this challenge, we explored the modulation of cellular RNA metabolic processes as an alternative [...] Read more.
Treatment options for viral infections are limited and viruses have proven adept at evolving resistance to many existing therapies, highlighting a significant vulnerability in our defenses. In response to this challenge, we explored the modulation of cellular RNA metabolic processes as an alternative paradigm to antiviral development. Previously, the small molecule 5342191 was identified as a potent inhibitor of HIV-1 replication by altering viral RNA accumulation at doses that minimally affect host gene expression. In this report, we document 5342191 as a potent inhibitor of adenovirus, coronavirus, and influenza replication. In each case, 5342191-mediated reduction in virus replication was associated with altered viral RNA accumulation and loss of viral structural protein expression. Interestingly, while resistant viruses were rapidly isolated for compounds targeting either virus-encoded proteases or polymerases, we have not yet isolated 5342191-resistant variants of coronavirus or influenza. As with HIV-1, 5342191’s inhibition of coronaviruses and influenza is mediated through the activation of specific cell signaling networks, including GPCR and/or MAPK signaling pathways that ultimately affect SR kinase expression. Together, these studies highlight the therapeutic potential of compounds that target cellular processes essential for the replication of multiple viruses. Not only do these compounds hold promise as broad-spectrum antivirals, but they also offer the potential of greater resilience in combating viral infections. Full article
(This article belongs to the Special Issue Viral Replication Inhibitors)
►▼ Show Figures

Figure 1

12 pages, 1046 KiB  
Article
Predictive Efficacy of Dual Therapies Combining Integrase Strand Transfer Inhibitors with Second-Generation Non-Nucleoside Reverse Transcriptase Inhibitors Following HIV-1 Treatment Failure in Cameroon: Implications for the Use of a Long-Acting Therapeutic Strategy in Low- and Middle-Income Countries
by Davy-Hyacinthe Gouissi Anguechia, Yagai Bouba, Ezechiel Ngoufack Jagni Semengue, Aude Christelle Ka’e, Désiré Takou, Collins Ambe Chenwi, Grace Beloumou, Alex Durand Nka, Ulrich Roland Basseck Wome, Maria Mercedes Santoro, Francesca Ceccherini-Silberstein, Adawaye Chatté, Carla Montesano, Giulia Cappelli, Vittorio Colizzi, Alexis Ndjolo, Dora Mbanya, Nicaise Ndembi, Carlo-Federico Perno and Joseph Fokam
Viruses 2024, 16(12), 1853; https://doi.org/10.3390/v16121853 - 29 Nov 2024
Viewed by 906
Abstract
Dual therapies (DT) combining integrase strand transfer inhibitors (INSTIs) with second-generation non-nucleoside reverse transcriptase inhibitors (2nd-Gen-NNRTIs) offer new possibilities for HIV treatment to improve adherence. However, drug resistance associated mutations (RAMs) to prior antiretrovirals may jeopardize the efficacy of DT. We herein describe [...] Read more.
Dual therapies (DT) combining integrase strand transfer inhibitors (INSTIs) with second-generation non-nucleoside reverse transcriptase inhibitors (2nd-Gen-NNRTIs) offer new possibilities for HIV treatment to improve adherence. However, drug resistance associated mutations (RAMs) to prior antiretrovirals may jeopardize the efficacy of DT. We herein describe the predicted efficacy of DT combining INSTIs + 2nd-Gen-NNRTI following treatment failure among Cameroonian patients. We genotyped the HIV-1 pol gene using Sanger sequencing and assessed acquired RAMs to NNRTIs and INSTIs in patients failing treatment from March 2019 to December 2023. Drug susceptibility was interpreted using Stanford HIVdb v9.5, and statistical analyses were performed using SPSS v22. Of 130 successfully genotyped participants (median age (IQR): 38 (27–46) years; 59.2% female), 92.3% had RAMs to NNRTIs and 1.5% to INSTIs. Prevailing RAMs were Y181C (32.3%) among NNRTIs and R263K (0.7%) among INSTIs. Among 2nd-Gen-NNRTIs, etravirine, doravirine and rilpivirine had 43.85%, 41.54% and 38.46% genotypic sensitivity, respectively. Among INSTIs, we found 97.69% efficacy for dolutegravir/bictegravir, 96.15% for cabotegravir and 92.31% for elvitegravir/raltegravir. The overall predictive efficacy of DT was lower among participants who failed 1st-Gen-NNRTI (p < 0.001); with etravirine + dolutegravir/bictegravir combination showing the highest score (43.8%). Conclusively, DT combining INSTIs + 2nd-Gen-NNRTIs might be suboptimal in the context of previous ART failure, especially with NNRTI-based treatment in low- and middle-income countries. The general data clearly indicate that without resistance testing, it is nearly impossible to use long-acting dual therapies in previously failing patients. Full article
(This article belongs to the Special Issue Viral Replication Inhibitors)
►▼ Show Figures

Figure 1

19 pages, 2443 KiB  
Article
Combining RNA Interference and RIG-I Activation to Inhibit Hepatitis E Virus Replication
by Mathias Ziersch, Dominik Harms, Lena Neumair, Anke Kurreck, Reimar Johne, C.-Thomas Bock and Jens Kurreck
Viruses 2024, 16(9), 1378; https://doi.org/10.3390/v16091378 - 29 Aug 2024
Viewed by 1341
Abstract
Hepatitis E virus (HEV) poses a significant global health threat, with an estimated 20 million infections occurring annually. Despite being a self-limiting illness, in most cases, HEV infection can lead to severe outcomes, particularly in pregnant women and individuals with pre-existing liver disease. [...] Read more.
Hepatitis E virus (HEV) poses a significant global health threat, with an estimated 20 million infections occurring annually. Despite being a self-limiting illness, in most cases, HEV infection can lead to severe outcomes, particularly in pregnant women and individuals with pre-existing liver disease. In the absence of specific antiviral treatments, the exploration of RNAi interference (RNAi) as a targeted strategy provides valuable insights for urgently needed therapeutic interventions against Hepatitis E. We designed small interfering RNAs (siRNAs) against HEV, which target the helicase domain and the open reading frame 3 (ORF3). These target regions will reduce the risk of viral escape through mutations, as they belong to the most conserved regions in the HEV genome. The siRNAs targeting the ORF3 efficiently inhibited viral replication in A549 cells after HEV infection. Importantly, the siRNA was also highly effective at inhibiting HEV in the persistently infected A549 cell line, which provides a suitable model for chronic infection in patients. Furthermore, we showed that a 5′ triphosphate modification on the siRNA sense strand activates the RIG-I receptor, a cytoplasmic pattern recognition receptor that recognizes viral RNA. Upon activation, RIG-I triggers a signaling cascade, effectively suppressing HEV replication. This dual-action strategy, combining the activation of the adaptive immune response and the inherent RNAi pathway, inhibits HEV replication successfully and may lead to the development of new therapies. Full article
(This article belongs to the Special Issue Viral Replication Inhibitors)
►▼ Show Figures

Figure 1

22 pages, 3562 KiB  
Article
Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling
by Nadine Alvarez, Gregory C. Adam, John A. Howe, Vijeta Sharma, Matthew D. Zimmerman, Enriko Dolgov, Risha Rasheed, Fatima Nizar, Khushboo Sahay, Andrew M. Nelson, Steven Park, Xiaoyan Zhou, Christine Burlein, John F. Fay, Daniel V. Iwamoto, Carolyn M. Bahnck-Teets, Krista L. Getty, Shih Lin Goh, Imad Salhab, Keith Smith, Christopher W. Boyce, Tamara D. Cabalu, Nicholas Murgolo, Nicholas G. Fox, Todd W. Mayhood, Valerie W. Shurtleff, Mark E. Layton, Craig A. Parish, John A. McCauley, David B. Olsen and David S. Perlinadd Show full author list remove Hide full author list
Viruses 2024, 16(7), 1158; https://doi.org/10.3390/v16071158 - 18 Jul 2024
Viewed by 2078
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as [...] Read more.
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After the extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction in viral burdens by >6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice). Full article
(This article belongs to the Special Issue Viral Replication Inhibitors)
►▼ Show Figures

Graphical abstract

14 pages, 2298 KiB  
Article
No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials
by Charlotte Hedskog, Christoph D. Spinner, Ulrike Protzer, Dieter Hoffmann, Chunkyu Ko, Robert L. Gottlieb, Medhat Askar, Meta Roestenberg, Jutte J. C. de Vries, Ellen C. Carbo, Ross Martin, Jiani Li, Dong Han, Lauren Rodriguez, Aiyappa Parvangada, Jason K. Perry, Ricard Ferrer, Andrés Antón, Cristina Andrés, Vanessa Casares, Huldrych F. Günthard, Michael Huber, Grace A. McComsey, Navid Sadri, Judith A. Aberg, Harm van Bakel and Danielle P. Porteradd Show full author list remove Hide full author list
Viruses 2024, 16(4), 546; https://doi.org/10.3390/v16040546 - 31 Mar 2024
Cited by 1 | Viewed by 2184
Abstract
Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV [...] Read more.
Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients. Full article
(This article belongs to the Special Issue Viral Replication Inhibitors)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-6
Back to TopTop