Drug-Repositioning Opportunities for Antiviral Therapy: Volume 2

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 April 2023) | Viewed by 8580

Special Issue Editor

Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, LU Leuven, Leuven, Belgium
Interests: herpesviruses; poxviruses; DNA tumor viruses; antiviral agents; drug-resistance; 3D culture models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With the emergence of COVID-19 in China in December 2019 and of the monkeypox virus in Europe in May 2022, viral infections have a high risk of causing a public health crisis. The novel coronavirus SARS-CoV-2 has created awareness that the appearance of new transmissible viruses is a global risk with an enormous social, health, and economic impact. Although WHO does not consider that the multi-country monkeypox outbreak currently constitutes a public health emergency of international concern, cases have increasingly been detected outside West and Central African countries where monkeypox is endemic.

Several viruses, such as Ebola virus, MERS-CoV, Nipah virus, SARS-CoV-2, and human monkeypox (hMPXV) among others, are recognized as emerging viruses of global threat and as top priorities requiring the development of strategies for prevention and treatment. On the other hand, several well-known viruses continue to cause significant morbidity and mortality, as exemplified by human cytomegalovirus in immunocompromised hosts and in neonates.

There is a continuing and growing need to develop new antiviral strategies that result in increased selectivity (i.e., lower toxicity and greater activity) and higher drug-resistance barriers to managing viral infections. Although significant efforts have been done leading to the approval of new antivirals, the identification of druggable targets, the development of direct-acting antivirals (DAA) and host-directed antiviral (HDA) candidates, and repurposed drugs remains a priority.

In this Special Issue, a special emphasis will be given to the investigation of drug repurposing as an antiviral strategy to combat emerging and re-emerging viral diseases. Drug repurposing, also known as redirecting, repurposing, repositioning, and re-profiling, is an alternative to the classical process of development of antivirals. Drug repurposing, the process of identifying new uses for existing or candidate drugs, is a fast and cost-effective method that can overcome traditional de novo drug discovery. This process can be very useful in emergencies, such as the one caused by COVID-19. The drug repurposing approach has identified some promising drug candidates for different viruses like Ebola, ZIKA, dengue, influenza, HIV, herpes simplex virus (HSV), CMV, and SARS-CoV-2 infections.

As a follow-up of the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy run in 2020, this Special Issue will focus on the progress over the past 2 years in drug repurposing as an approach to find candidate antiviral agents within a short span of time to overcome the challenges of drug development and the global threat of emerging and re-emerging viral infectious diseases. We welcome original research and comprehensive review articles presenting recent progress, challenges, and future perspectives of drug repurposing in antiviral drug discovery.

Prof. Dr. Graciela Andrei
Guest Editor

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Keywords

  • drug repurposing
  • emerging and re-emerging viral diseases
  • antiviral strategies
  • antiviral drug discovery
  • druggable antiviral targets
  • direct acting antivirals
  • host-directed antivirals
  • drug-resistant viruses

Related Special Issue

Published Papers (4 papers)

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Research

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12 pages, 3493 KiB  
Article
Repurposing of Doramectin as a New Anti-Zika Virus Agent
by Yujia Zhu, Minqi Liang, Jianchen Yu, Bingzhi Zhang, Ge Zhu, Yun Huang, Zhenjian He and Jie Yuan
Viruses 2023, 15(5), 1068; https://doi.org/10.3390/v15051068 - 27 Apr 2023
Cited by 3 | Viewed by 1300
Abstract
Zika virus (ZIKV), belonging to the Flavivirus family and mainly transmitted by mosquitoes, causes a variety of adverse outcomes, including Guillain-Barré syndrome, microcephaly, and meningoencephalitis. However, there are no approved vaccines or drugs available for ZIKV. The discovery and research on drugs for [...] Read more.
Zika virus (ZIKV), belonging to the Flavivirus family and mainly transmitted by mosquitoes, causes a variety of adverse outcomes, including Guillain-Barré syndrome, microcephaly, and meningoencephalitis. However, there are no approved vaccines or drugs available for ZIKV. The discovery and research on drugs for ZIKV are still essential. In this study, we identified doramectin, an approved veterinary antiparasitic drug, as a novel anti-ZIKV agent (EC50 value from 0.85 μM to 3.00 μM) with low cytotoxicity (CC50 > 50 μM) in multiple cellular models. The expression of ZIKV proteins also decreased significantly under the treatment of doramectin. Further study showed that doramectin directly interacted with the key enzyme for ZIKV genome replication, RNA-dependent RNA polymerase (RdRp), with a stronger affinity (Kd = 16.9 μM), which may be related to the effect on ZIKV replication. These results suggested that doramectin might serve as a promising drug candidate for anti-ZIKV. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy: Volume 2)
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9 pages, 1453 KiB  
Article
Search of Novel Small Molecule Inhibitors for the Main Protease of SARS-CoV-2
by Wenfa Zhang and Sheng-Xiang Lin
Viruses 2023, 15(2), 580; https://doi.org/10.3390/v15020580 - 20 Feb 2023
Cited by 4 | Viewed by 1589
Abstract
The current outbreak of coronavirus disease 2019 (COVID-19) has prompted the necessity of efficient treatment strategies. The COVID-19 pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Main protease (Mpro), also called 3-chymotrypsin-like protease (3CL protease), plays an essential role [...] Read more.
The current outbreak of coronavirus disease 2019 (COVID-19) has prompted the necessity of efficient treatment strategies. The COVID-19 pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Main protease (Mpro), also called 3-chymotrypsin-like protease (3CL protease), plays an essential role in cleaving virus polyproteins for the functional replication complex. Therefore, Mpro is a promising drug target for COVID-19 therapy. Through molecular modelling, docking and a protease activity assay, we found four novel inhibitors targeting Mpro with the half maximal inhibitory concentration (IC50) and their binding affinities shown by the dissociation constants (KDs). Our new inhibitors CB-21, CB-25, CP-1 and LC24-20 have IC50s at 14.88 µM (95% Confidence Interval (95% CI): 10.35 µM to 20.48 µM), 22.74 µM (95% CI: 13.01 µM to 38.16 µM), 18.54µM (95% CI: 6.54 µM to 36.30 µM) and 32.87µM (95% CI: 18.37 µM to 54.80 µM)), respectively. The evaluation of interactions suggested that each inhibitor has a hydrogen bond or hydrophobic interactions with important residues, including the most essential catalytic residues: His41 and Cys145. All the four inhibitors have a much higher 50% lethal dose (LD50) compared with the well-known Mpro inhibitor GC376, demonstrating its low toxicity. These four inhibitors can be potential drug candidates for further in vitro and in vivo studies against COVID-19. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy: Volume 2)
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18 pages, 4783 KiB  
Article
A Transcriptomics-Based Bioinformatics Approach for Identification and In Vitro Screening of FDA-Approved Drugs for Repurposing against Dengue Virus-2
by Madhura Punekar, Bhagyashri Kasabe, Poonam Patil, Mahadeo B. Kakade, Deepti Parashar, Kalichamy Alagarasu and Sarah Cherian
Viruses 2022, 14(10), 2150; https://doi.org/10.3390/v14102150 - 29 Sep 2022
Cited by 6 | Viewed by 2793
Abstract
The rising incidence of dengue virus (DENV) infections in the tropical and sub-tropical regions of the world emphasizes the need to identify effective therapeutic drugs against the disease. Repurposing of drugs has emerged as a novel concept to combat pathogens. In this study, [...] Read more.
The rising incidence of dengue virus (DENV) infections in the tropical and sub-tropical regions of the world emphasizes the need to identify effective therapeutic drugs against the disease. Repurposing of drugs has emerged as a novel concept to combat pathogens. In this study, we employed a transcriptomics-based bioinformatics approach for drug identification against DENV. Gene expression omnibus datasets from patients with different grades of dengue disease severity and healthy controls were used to identify differentially expressed genes in dengue cases, which were then applied to the query tool of Connectivity Map to identify the inverse gene–disease–drug relationship. A total of sixteen identified drugs were investigated for their prophylactic, virucidal, and therapeutic effects against DENV. Focus-forming unit assay and quantitative RT-PCR were used to evaluate the antiviral activity. Results revealed that five compounds, viz., resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat, have significant anti-DENV activity. Further, molecular docking studies showed that these drugs can interact with a variety of protein targets of DENV, including the glycoprotein, the NS5 RdRp, NS2B-NS3 protease, and NS5 methyltransferase The in vitro and in silico results, therefore, reveal that these drugs have the ability to decrease DENV-2 production, suggesting that these drugs or their derivatives could be attempted as therapeutic agents against DENV infections. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy: Volume 2)
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Review

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46 pages, 27660 KiB  
Review
Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases
by Rima Hajjo, Dima A. Sabbah, Osama H. Abusara, Reham Kharmah and Sanaa Bardaweel
Viruses 2023, 15(2), 568; https://doi.org/10.3390/v15020568 - 19 Feb 2023
Cited by 2 | Viewed by 2333
Abstract
Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly [...] Read more.
Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy: Volume 2)
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