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Viruses
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Drug-Repositioning Opportunities for Antiviral Therapy
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Drug-Repositioning Opportunities for Antiviral Therapy

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 (20 December 2020) | Viewed by 81327

Special Issue Editor

Prof. Dr. Graciela Andrei

E-Mail Website
Guest 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, it is clear that viral infections have a high risk of causing public health crisis. This novel coronavirus has created awareness that the appearance of new transmissible viruses is a global risk with an enormous social, health, and economic impact. 

Several viruses, such as Ebola virus, MERS-CoV, Nipah virus, and COVID-19, among other, 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 familiar 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 manage viral infections. Although significant efforts have been done leading to the approval of about 30 antivirals, the identification of druggable targets, the development of direct acting antivirals (DAA) and host-directed antiviral (HDA) candidates, and repurposed drugs remain a priority.

In this Special issue, a special emphasis will be given to the investigation of drug repurposing as a novel 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 currently caused by Covid-19. The drug repurposing approach has identified some promising drug candidates for different viral diseases like Ebola, ZIKA, dengue, influenza, HIV, herpes simplex virus (HSV), CMV, and Covid-19 infections.

This Special issue aims to explore 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

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

  • 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

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Published Papers (12 papers)

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Research

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11 pages, 1940 KiB  
Article
Resveratrol Inhibits HCoV-229E and SARS-CoV-2 Coronavirus Replication In Vitro
by Sébastien Pasquereau, Zeina Nehme, Sandy Haidar Ahmad, Fadoua Daouad, Jeanne Van Assche, Clémentine Wallet, Christian Schwartz, Olivier Rohr, Stéphanie Morot-Bizot and Georges Herbein
Viruses 2021, 13(2), 354; https://doi.org/10.3390/v13020354 - 23 Feb 2021
Cited by 73 | Viewed by 5857
Abstract
A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drug repurposing embodies a rich and rapid drug discovery landscape, where candidate drug [...] Read more.
A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drug repurposing embodies a rich and rapid drug discovery landscape, where candidate drug compounds could be identified and optimized. To this end, we tested seven compounds for their ability to reduce replication of human coronavirus (HCoV)-229E, another member of the coronavirus family. Among these seven drugs tested, four of them, namely rapamycin, disulfiram, loperamide and valproic acid, were highly cytotoxic and did not warrant further testing. In contrast, we observed a reduction of the viral titer by 80% with resveratrol (50% effective concentration (EC50) = 4.6 µM) and lopinavir/ritonavir (EC50 = 8.8 µM) and by 60% with chloroquine (EC50 = 5 µM) with very limited cytotoxicity. Among these three drugs, resveratrol was less cytotoxic (cytotoxic concentration 50 (CC50) = 210 µM) than lopinavir/ritonavir (CC50 = 102 µM) and chloroquine (CC50 = 67 µM). Thus, among the seven drugs tested against HCoV-229E, resveratrol demonstrated the optimal antiviral response with low cytotoxicity with a selectivity index (SI) of 45.65. Similarly, among the three drugs with an anti-HCoV-229E activity, namely lopinavir/ritonavir, chloroquine and resveratrol, only the latter showed a reduction of the viral titer on SARS-CoV-2 with reduced cytotoxicity. This opens the door to further evaluation to fight Covid-19. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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20 pages, 6295 KiB  
Article
Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections
by Ben M. Flude, Giulio Nannetti, Paige Mitchell, Nina Compton, Chloe Richards, Meike Heurich, Andrea Brancale, Salvatore Ferla and Marcella Bassetto
Viruses 2021, 13(2), 312; https://doi.org/10.3390/v13020312 - 17 Feb 2021
Cited by 20 | Viewed by 4415
Abstract
MASP-2, mannose-binding protein-associated serine protease 2, is a key enzyme in the lectin pathway of complement activation. Hyperactivation of this protein by human coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 has been found to contribute to aberrant complement activation in patients, leading to aggravated lung [...] Read more.
MASP-2, mannose-binding protein-associated serine protease 2, is a key enzyme in the lectin pathway of complement activation. Hyperactivation of this protein by human coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 has been found to contribute to aberrant complement activation in patients, leading to aggravated lung injury with potentially fatal consequences. This hyperactivation is triggered in the lungs through a conserved, direct interaction between MASP-2 and coronavirus nucleocapsid (N) proteins. Blocking this interaction with monoclonal antibodies and interfering directly with the catalytic activity of MASP-2, have been found to alleviate coronavirus-induced lung injury both in vitro and in vivo. In this study, a virtual library of 8736 licensed drugs and clinical agents has been screened in silico according to two parallel strategies. The first strategy aims at identifying direct inhibitors of MASP-2 catalytic activity, while the second strategy focusses on finding protein-protein interaction inhibitors (PPIs) of MASP-2 and coronaviral N proteins. Such agents could represent promising support treatment options to prevent lung injury and reduce mortality rates of infections caused by both present and future-emerging coronaviruses. Forty-six drug repurposing candidates were purchased and, for the ones selected as potential direct inhibitors of MASP-2, a preliminary in vitro assay was conducted to assess their interference with the lectin pathway of complement activation. Some of the tested agents displayed a dose-response inhibitory activity of the lectin pathway, potentially providing the basis for a viable support strategy to prevent the severe complications of coronavirus infections. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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10 pages, 8621 KiB  
Article
Quinacrine, an Antimalarial Drug with Strong Activity Inhibiting SARS-CoV-2 Viral Replication In Vitro
by Mónica Salas Rojas, Raúl Silva Garcia, Estela Bini, Verónica Pérez de la Cruz, Juan Carlos León Contreras, Rogelio Hernández Pando, Fernando Bastida Gonzalez, Eduardo Davila-Gonzalez, Mario Orozco Morales, Armando Gamboa Domínguez, Julio Sotelo and Benjamín Pineda
Viruses 2021, 13(1), 121; https://doi.org/10.3390/v13010121 - 17 Jan 2021
Cited by 19 | Viewed by 3939
Abstract
Quinacrine (Qx), a molecule used as an antimalarial, has shown anticancer, antiprion, and antiviral activity. The most relevant antiviral activities of Qx are related to its ability to raise pH in acidic organelles, diminishing viral enzymatic activity for viral cell entry, and its [...] Read more.
Quinacrine (Qx), a molecule used as an antimalarial, has shown anticancer, antiprion, and antiviral activity. The most relevant antiviral activities of Qx are related to its ability to raise pH in acidic organelles, diminishing viral enzymatic activity for viral cell entry, and its ability to bind to viral DNA and RNA. Moreover, Qx has been used as an immunomodulator in cutaneous lupus erythematosus and various rheumatological diseases, by inhibiting phospholipase A2 modulating the Th1/Th2 response. The aim of this study was to evaluate the potential antiviral effect of Qx against denominated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Vero E6 cells. The cytotoxicity of Qx in Vero E6 cells was determined by the MTT assay. Afterwards, Vero E6 cells were infected with SARS-CoV-2 at different multiplicities of infections (MOIs) of 0.1 and 0.01 in the presence of Qx (0–30 µM) to determinate the half maximal effective concentration (EC50). After 48 h, the effect of Qx against SARS-CoV-2 was assessed by viral cytotoxicity and viral copy numbers, the last were determined by digital real-time RT-PCR (ddRT-PCR). Additionally, electron and confocal microscopy of Vero E6 cells infected and treated with Qx was studied. Our data show that Qx reduces SARS-CoV-2 virus replication and virus cytotoxicity, apparently by inhibition of viral ensemble, as observed by ultrastructural images, suggesting that Qx could be a potential drug for further clinical studies against coronavirus disease 2019 (COVID-19) infection. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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12 pages, 2805 KiB  
Article
Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug
by Camilla Isgrò, Anna Maria Sardanelli and Luigi Leonardo Palese
Viruses 2021, 13(1), 106; https://doi.org/10.3390/v13010106 - 13 Jan 2021
Cited by 9 | Viewed by 13667
Abstract
In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity [...] Read more.
In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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12 pages, 1845 KiB  
Article
Fluoroquinolone Antibiotics Exhibit Low Antiviral Activity against SARS-CoV-2 and MERS-CoV
by Stacey L. P. Scroggs, Danielle K. Offerdahl, Dylan P. Flather, Ciera N. Morris, Benjamin L. Kendall, Rebecca M. Broeckel, Paul A. Beare and Marshall E. Bloom
Viruses 2021, 13(1), 8; https://doi.org/10.3390/v13010008 - 23 Dec 2020
Cited by 27 | Viewed by 4679
Abstract
Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero [...] Read more.
Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC50) of 126.4 μM in Vero cells. Enoxacin also suppressed the replication of MERS-CoV-2 in Vero cells at high micromolar concentrations. Cellular toxicity of levofloxacin was not found in either cell type. In Vero cells, minimal toxicity was observed following treatment with ≥37.5 μM enoxacin and 600 μM ciprofloxacin. Toxicity in both cell types was detected after moxifloxacin treatment of ≥300 μM. In summary, these results suggest that the ability of fluoroquinolones to suppress SARS-CoV-2 and MERS-CoV replication in cultured cells is limited. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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11 pages, 277 KiB  
Article
Target-Centered Drug Repurposing Predictions of Human Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Protease Serine Subtype 2 (TMPRSS2) Interacting Approved Drugs for Coronavirus Disease 2019 (COVID-19) Treatment through a Drug-Target Interaction Deep Learning Model
by Yoonjung Choi, Bonggun Shin, Keunsoo Kang, Sungsoo Park and Bo Ram Beck
Viruses 2020, 12(11), 1325; https://doi.org/10.3390/v12111325 - 18 Nov 2020
Cited by 29 | Viewed by 4464
Abstract
Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, [...] Read more.
Previously, our group predicted commercially available Food and Drug Administration (FDA) approved drugs that can inhibit each step of the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using a deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI). Unfortunately, additional clinically significant treatment options since the approval of remdesivir are scarce. To overcome the current coronavirus disease 2019 (COVID-19) more efficiently, a treatment strategy that controls not only SARS-CoV-2 replication but also the host entry step should be considered. In this study, we used MT-DTI to predict FDA approved drugs that may have strong affinities for the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease serine 2 (TMPRSS2) which are essential for viral entry to the host cell. Of the 460 drugs with Kd of less than 100 nM for the ACE2 receptor, 17 drugs overlapped with drugs that inhibit the interaction of ACE2 and SARS-CoV-2 spike reported in the NCATS OpenData portal. Among them, enalaprilat, an ACE inhibitor, showed a Kd value of 1.5 nM against the ACE2. Furthermore, three of the top 30 drugs with strong affinity prediction for the TMPRSS2 are anti-hepatitis C virus (HCV) drugs, including ombitasvir, daclatasvir, and paritaprevir. Notably, of the top 30 drugs, AT1R blocker eprosartan and neuropsychiatric drug lisuride showed similar gene expression profiles to potential TMPRSS2 inhibitors. Collectively, we suggest that drugs predicted to have strong inhibitory potencies to ACE2 and TMPRSS2 through the DTI model should be considered as potential drug repurposing candidates for COVID-19. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
23 pages, 1852 KiB  
Article
Old Drugs with New Tricks: Efficacy of Fluoroquinolones to Suppress Replication of Flaviviruses
by Stacey L. P. Scroggs, Christy C. Andrade, Ramesh Chinnasamy, Sasha R. Azar, Erin E. Schirtzinger, Erin I. Garcia, Jeffrey B. Arterburn, Kathryn A. Hanley and Shannan L. Rossi
Viruses 2020, 12(9), 1022; https://doi.org/10.3390/v12091022 - 13 Sep 2020
Cited by 10 | Viewed by 3155
Abstract
Repurposing FDA-approved compounds could provide the fastest route to alleviate the burden of disease caused by flaviviruses. In this study, three fluoroquinolones, enoxacin, difloxacin and ciprofloxacin, curtailed replication of flaviviruses Zika (ZIKV), dengue (DENV), Langat (LGTV) and Modoc (MODV) in HEK-293 cells at [...] Read more.
Repurposing FDA-approved compounds could provide the fastest route to alleviate the burden of disease caused by flaviviruses. In this study, three fluoroquinolones, enoxacin, difloxacin and ciprofloxacin, curtailed replication of flaviviruses Zika (ZIKV), dengue (DENV), Langat (LGTV) and Modoc (MODV) in HEK-293 cells at low micromolar concentrations. Time-of-addition assays suggested that enoxacin suppressed ZIKV replication at an intermediate step in the virus life cycle, whereas ciprofloxacin and difloxacin had a wider window of efficacy. A129 mice infected with 1 × 105 plaque-forming units (pfu) ZIKV FSS13025 (n = 20) or phosphate buffered saline (PBS) (n = 11) on day 0 and treated with enoxacin at 10 mg/kg or 15 mg/kg or diluent orally twice daily on days 1–5 did not differ in weight change or virus titer in serum or brain. However, mice treated with enoxacin showed a significant, five-fold decrease in ZIKV titer in testes relative to controls. Mice infected with 1 × 102 pfu ZIKV (n = 13) or PBS (n = 13) on day 0 and treated with 15 mg/kg oral enoxacin or diluent twice daily pre-treatment and days 1–5 post-treatment also did not differ in weight and viral load in the serum, brain, and liver, but mice treated with enoxacin showed a significant, 2.5-fold decrease in ZIKV titer in testes relative to controls. ZIKV can be sexually transmitted, so reduction of titer in the testes by enoxacin should be further investigated. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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18 pages, 4076 KiB  
Article
Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19)
by Shuofeng Yuan, Chris Chun-Yiu Chan, Kenn Ka-Heng Chik, Jessica Oi-Ling Tsang, Ronghui Liang, Jianli Cao, Kaiming Tang, Jian-Piao Cai, Zi-Wei Ye, Feifei Yin, Kelvin Kai-Wang To, Hin Chu, Dong-Yan Jin, Ivan Fan-Ngai Hung, Kwok-Yung Yuen and Jasper Fuk-Woo Chan
Viruses 2020, 12(6), 628; https://doi.org/10.3390/v12060628 - 10 Jun 2020
Cited by 49 | Viewed by 6247
Abstract
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities [...] Read more.
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-β1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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25 pages, 3617 KiB  
Article
Potential Drugs Targeting Early Innate Immune Evasion of SARS-Coronavirus 2 via 2’-O-Methylation of Viral RNA
by José Antonio Encinar and Javier A. Menendez
Viruses 2020, 12(5), 525; https://doi.org/10.3390/v12050525 - 10 May 2020
Cited by 71 | Viewed by 10851
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a [...] Read more.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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Review

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24 pages, 1121 KiB  
Review
Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak
by Zheng Yao Low, Isra Ahmad Farouk and Sunil Kumar Lal
Viruses 2020, 12(9), 1058; https://doi.org/10.3390/v12091058 - 22 Sep 2020
Cited by 69 | Viewed by 7659
Abstract
Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for [...] Read more.
Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing’s syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, Ivermectin and Baricitinib shows good potential for COVID-19 treatment. This can crucially aid in resolving outbreaks in urgent times of need. This review discusses the past success in drug repositioning, the current technological advancement in the field, drug repositioning for personalised medicine and the ongoing research on newly emerging drugs under consideration for the COVID-19 treatment. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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15 pages, 592 KiB  
Review
Repurposing Antiviral Protease Inhibitors Using Extracellular Vesicles for Potential Therapy of COVID-19
by Santosh Kumar, Kaining Zhi, Ahona Mukherji and Kelli Gerth
Viruses 2020, 12(5), 486; https://doi.org/10.3390/v12050486 - 26 Apr 2020
Cited by 96 | Viewed by 10550
Abstract
In January 2020, Chinese health agencies reported an outbreak of a novel coronavirus-2 (CoV-2) which can lead to severe acute respiratory syndrome (SARS). The virus, which belongs to the coronavirus family (SARS-CoV-2), was named coronavirus disease 2019 (COVID-19) and declared a pandemic by [...] Read more.
In January 2020, Chinese health agencies reported an outbreak of a novel coronavirus-2 (CoV-2) which can lead to severe acute respiratory syndrome (SARS). The virus, which belongs to the coronavirus family (SARS-CoV-2), was named coronavirus disease 2019 (COVID-19) and declared a pandemic by the World Health Organization (WHO). Full-length genome sequences of SARS-CoV-2 showed 79.6% sequence identity to SARS-CoV, with 96% identity to a bat coronavirus at the whole-genome level. COVID-19 has caused over 133,000 deaths and there are over 2 million total confirmed cases as of 15 April 2020. Current treatment plans are still under investigation due to a lack of understanding of COVID-19. One potential mechanism to slow disease progression is the use of antiviral drugs to either block the entry of the virus or interfere with viral replication and maturation. Currently, antiviral drugs, including chloroquine/hydroxychloroquine, remdesivir, and lopinavir/ritonavir, have shown effective inhibition of SARS-CoV-2 in vitro. Due to the high dose needed and narrow therapeutic window, many patients are experiencing severe side effects with the above drugs. Hence, repurposing these drugs with a proper formulation is needed to improve the safety and efficacy for COVID-19 treatment. Extracellular vesicles (EVs) are a family of natural carriers in the human body. They play a critical role in cell-to-cell communications. EVs can be used as unique drug carriers to deliver protease inhibitors to treat COVID-19. EVs may provide targeted delivery of protease inhibitors, with fewer systemic side effects. More importantly, EVs are eligible for major aseptic processing and can be upscaled for mass production. Currently, the FDA is facilitating applications to treat COVID-19, which provides a very good chance to use EVs to contribute in this combat. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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Other

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15 pages, 3286 KiB  
Hypothesis
In Silico Insights into the SARS CoV-2 Main Protease Suggest NADH Endogenous Defences in the Control of the Pandemic Coronavirus Infection
by Annamaria Martorana, Carla Gentile and Antonino Lauria
Viruses 2020, 12(8), 805; https://doi.org/10.3390/v12080805 - 26 Jul 2020
Cited by 13 | Viewed by 4174
Abstract
COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used [...] Read more.
COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (MPRO) inhibitors that fit in the catalytic binding site of SARS CoV-2 MPRO. Several selected structures are NAD-like derivatives, suggesting a relevant role of these molecules in the modulation of SARS CoV-2 infection in conditions of cell chronic oxidative stress. Increased catabolism of NAD(H) during protein ribosylation in the DNA damage repair process may explain the greater susceptibility of the elderly population to the acute respiratory symptoms of COVID-19. The molecular modelling studies proposed herein agree with this hypothesis. Full article
(This article belongs to the Special Issue Drug-Repositioning Opportunities for Antiviral Therapy)
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