OPINION published: 16 February 2022 doi: 10.3389/fmicb.2022.843587 What Should Be Learned From Repurposed Antivirals Against SARS-CoV-2? Miguel Angel Martinez* IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain Keywords: antiviral, repurposed drugs, virus therapy, SARS-CoV-2, emerging viruses Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in 2019, more than 270 million infections have been reported, and the death toll from the associated coronavirus disease 2019 (COVID-19) has reached 5.5 million. The magnitude of this pandemic has encouraged the repurposing of numerous drugs, with the aim of rapidly curbing the morbidity, mortality, and spread of this new disease. However, this approach has had limited success. Only vaccine development and the repurposing of dexamethasone have impacted COVID-19 severity. Drug repurposing is, perhaps, an effective strategy for identifying antivirals, but there are no shortcuts for drug development. The identification of effective drugs, regardless of previous approval, requires time and funding to confirm and understand the drug target, the drug’s toxicity, and its proper use. The lessons learned with COVID-19 should provide a roadmap for approaching drug discovery, when confronting SARS-CoV-2 and other current and future viral threats. From the beginning of the SARS-CoV-2 pandemic in China, it was clear that severe COVID-19 was an inflammatory acute respiratory distress syndrome (ARDS). Indeed, early in the pandemic, COVID-19 progression from mild to moderate to severe was associated with immune dysfunction, hyper-inflammatory response, and sepsis (Zhou et al., 2020). Later studies showed that some patients infected with SARS-CoV-2 developed severe pneumonia and ARDS (Grant et al., 2021). Edited by: Consequently, both antiviral and immunomodulatory drugs were contemplated and administered Chunfu Zheng, early in the pandemic (Martinez, 2020; Cross et al., 2021). Early studies (Tay et al., 2020) searched University of Calgary, Canada for parallelisms between SARS-CoV-2-related pneumonia and pneumonias connected to other Reviewed by: human coronavirus diseases, such as severe acute respiratory syndrome (SARS-CoV) and Middle Steven De Jonghe, East respiratory syndrome (MERS-CoV). However, the pathobiology of SARS-CoV-2-related KU Leuven, Belgium pneumonia seems to be distinct from pneumonia caused by other respiratory viral and bacterial *Correspondence: pathogens; the SARS-CoV-2-related pneumonia displays unusual clinical features and has a longer Miguel Angel Martinez clinical course than severe pneumonia (Gattinoni et al., 2020; Grant et al., 2021). An accurate mmartinez@irsicaixa.es clinical characterization of SARS-CoV-2 infections, based on known clinical syndromes, is critical for the identification of effective therapies (Cross et al., 2021). Specialty section: Understandably, early in the SARS-CoV-2 pandemic, several repurposed drugs were This article was submitted to quickly translated to the clinic. However, over the 2 last years, the results have been Virology, rather poor (Edwards, 2020; Edwards and Hartung, 2021; Martinez, 2021). The repurposed a section of the journal drugs for combating COVID-19 were selected either without a hypothetical basis or with Frontiers in Microbiology mechanistic hypothetical approaches. Unfortunately, when those candidates were tested in Received: 26 December 2021 clinical studies, none proved effective against SARS-CoV-2. Given that the repurposed Accepted: 26 January 2022 drugs were optimized for a different target, dosage, or tissue, their pharmacology was Published: 16 February 2022 probably not appropriate for the new indication (Edwards, 2020; Dahlin et al., 2021). Citation: In addition, the cellular assays designed for repurposing antivirals, including phenotypic Martinez MA (2022) What Should Be Learned From Repurposed Antivirals and high-throughput screening assays, are frequently subject to interfering or undesirable Against SARS-CoV-2? bioactive mechanisms (Dahlin et al., 2021). Remarkably, most of the repurposed drugs Front. Microbiol. 13:843587. tested during this pandemic were administered off-label and outside of properly designed doi: 10.3389/fmicb.2022.843587 observational or clinical trials. However, unsuccessful approaches might reduce the public trust Frontiers in Microbiology | www.frontiersin.org 1 February 2022 | Volume 13 | Article 843587 Martinez Failing Repurposed Antivirals Against SARS-CoV-2 in evidence-based medicine (Cross et al., 2021). Therefore, (Agostini et al., 2018), such as SARS-CoV and MERS-CoV. clinical trials and methodologies for identifying effective drugs Moreover, it showed prophylactic and therapeutic efficacy in a should be designed based on methodologies with the highest rhesus macaque model of a MERS-CoV infection (de Wit et al., likelihood of success. 2020). However, the clinical efficacy of remdesivir for COVID- Antiviral drugs target key processes in the virus life cycle. 19 remains controversial. Several trials have found no significant These processes include virus cell entry, genome replication, differences between remdesivir-treated and control groups in translation, protein processing, and virus particle generation. the time-to-clinical-improvement or mortality (Yan and Muller, More than two-thirds of all antivirals approved for human use 2021). Previous work with remdesivir also showed impressive target viral enzymes, such as viral RNA/DNA polymerases and preclinical and animal-model results against Ebola virus (Warren viral proteases (De Clercq and Li, 2016; Tompa et al., 2021). et al., 2016); however, those results were not confirmed in clinical Importantly, in the last 30 years, no antiviral drug has been studies (Mulangu et al., 2019). approved in the absence of a specific viral target. Thus, perhaps In severe cases, SARS-CoV-2 induces an overexpression of the main drawback of the repurposed antiviral drugs that have inflammatory cytokines. Accordingly, immunomodulatory been tested unsuccessfully against SARS-CoV-2 has been the therapies, such as Anakinra (anti-interleukin 1b) and absence of an evident mechanism of action (Table 1). Tocilizumab (anti-interleukin 6), were repurposed for Hits from antiviral screening based on biochemical or cell- COVID-19. However, monotherapies with these compounds culture assays must be treated with skepticism. Chloroquine were unsuccessful. Remarkably, broad-spectrum immune- and hydroxychloroquine represent a clear example of modulators, such as dexamethasone or baricitinib (anti-Janus misinterpreted cell culture results. The efficacy of chloroquine kinase) have shown better efficacy in severe COVID-19 and hydroxychloroquine against SARS-CoV-2 in tissue cultures cases (Tomazini et al., 2020; Abani et al., 2021; Kalil et al., was determined with African green monkey kidney-derived 2021). The pathogenesis of COVID-19 is different from those Vero cells. However, when Vero cells were engineered to of other respiratory diseases. Consequently, repurposing express TMPRSS2, a cellular protease that activates SARS-CoV-2 immunomodulatory therapies might be more difficult than for entry into lung cells, the genetic manipulation rendered initially thought. Additionally, immunomodulatory therapies SARS-CoV-2–infected Vero cells insensitive to chloroquine that might be useful for severe COVID-19 might be harmful in (Hoffmann et al., 2020). Accordingly, chloroquine could not mild or moderate COVID-19, where the immune system can block SARS-CoV-2 infections in TMPRSS2-expressing human work effectively to control viral replication and disease (Cross lung Calu-3 cells; thus, chloroquine targets a viral activation et al., 2021). pathway that is not present in human lung cells. Therefore, the Historically, repurposing drugs has only been successful in drug is unlikely to protect against the spread of SARS-CoV-2. a few cases (Edwards, 2020). Examples are aspirin, for treating Another example of a misinterpretation of cell culture results coronary artery disease; erythromycin, for treating impaired was recently reported (Tummino et al., 2021) in a study that gastric motility; sildenafil for treating erectile dysfunction; demonstrated that phospholipidosis was a shared mechanism thalidomide for treating multiple myeloma; and imatinib for underlying the antiviral activity of many repurposed drugs treating gastrointestinal stromal tumors (Corsello et al., 2017). for SARS-CoV-2 (Tummino et al., 2021). Conversely, drugs Most of those achievements were serendipitous. Nevertheless, that were active against the same targets, but did not induce those chance discoveries have promoted systematic searches phospholipidosis, were not effective against viruses. Those results for other drugs that might be repurposed. These explorations strongly suggested that a failure to induce phospholipidosis could have mainly relied on high-throughput screening technologies explain why most drugs that were selected for repurposing to and computational modeling with large datasets (Edwards, date lacked clinical efficacy against SARS-CoV-2. In future 2020). Currently, several libraries of approved drugs are pandemics, the target specificity of candidate antivirals should available for rapid screening to identify candidates for be examined before initiating treatment to exclude non-specific repurposing against the targeted disease. Unfortunately, mechanisms during drug development. Target specificity should systematic, hypothesis-free, large-scale screening of these be accompanied by safety profiles and a determination of the drug libraries has yet to yield effective treatments for most pharmacokinetics/pharmacodynamics of selected drugs. Viruses targeted diseases. manipulate many cellular processes during their life-cycles; thus, Effective vaccines against SARS-CoV-2 have been developed when a tested drug modifies a cellular pathway, it frequently with extraordinary speediness. Vaccines have prevented COVID- leads to a false-positive hit. 19 development, but they have not generated sterilizing Even when a drug mechanism of action is known, the immunity in a significant percentage of individuals; thus, viral preclinical data must be interpreted with caution. At the transmission remains possible after a vaccination (Krammer, beginning of the SARS-CoV-2 pandemic, remdesivir, developed 2020; Cromer et al., 2021). The continuous emergence of by Gilead, was the most promising antiviral drug for combating SARS-CoV-2 variants, such as the Delta or Omicron variant, SARS-CoV-2. Initial interest in the drug was based on its has challenged the efficacy of current vaccines. The Omicron potency in cell culture models of SARS-CoV-2, including outbreak in southern Africa might be due to its capacity to primary human airway epithelial cells (Pruijssers et al., 2020). infect people that have been vaccinated or have recovered Moreover, remdesivir displayed specificity against the RNA- from COVID-19 caused by Delta and other variants. At this dependent RNA polymerase (RdRp) of other coronaviruses stage, there is a need for an antiviral that effectively combats Frontiers in Microbiology | www.frontiersin.org 2 February 2022 | Volume 13 | Article 843587 Martinez Failing Repurposed Antivirals Against SARS-CoV-2 TABLE 1 | Most relevant repurposed antiviral drugs against SARS-CoV-2. Antiviral drug Approved target disease Drug target COVID-19 clinical trial reference Favipiravir Influenza virus Virus RdRp Doi et al., 2020 Hydroxychloroquine Malaria Hemozoin biocrystallization Axfors et al., 2021; WHO Solidarity Trial Consortium, 2021 Ivermectin Antiparasitic Glutamate-gated chloride channels Baker and Reardon, 2021; Popp et al., 2021 Interferon beta-1a Multiple sclerosis Reduce inflammation WHO Solidarity Trial Consortium, 2021 Lopinavir HIV-1 Virus protease Cao et al., 2020; WHO Solidarity Trial Consortium, 2021 Remdesivir SARS-CoV-2 Virus RdRp Wang et al., 2020; WHO Solidarity Trial Consortium, 2021 TABLE 2 | Approved direct acting antiviral drugs against SARS-CoV-2. Antiviral drug Drug target Delivery References Molnupiravir Virus RdRp Oral Jayk Bernal et al., 2021 (MK-4482/EIDD-2801) Nirmatrelvir Virus main protease Oral Owen et al., 2021 (PF-07321332) Remdesivir Virus RdRp Intravenous Wang et al., 2020; WHO Solidarity Trial Consortium, 2021 (GS-5734) SARS-CoV-2 to prevent more severe disease, hospitalizations, variants are characterized by mutations in the viral spike protein and deaths. and other regions that are targeted by the immune system A combination of vaccines and antiviral drugs should and/or by vaccines. Nevertheless, it should not be overlooked be a powerful tool for controlling the morbidity, mortality, that monotherapy with any of these antivirals may induce viral and spread of SARS-CoV-2. Antivirals should target SARS- drug resistance. This has been a familiar problem with other virus CoV-2 infections early to prevent rapid viral replication. In infections, like HIV-1 and HCV, which require treatments with a addition to the approved antiviral, remdesivir, which is delivered combination of antiviral drugs. intravenously, two additional oral drugs, molnupiravir and The emergence of new human viruses, such as HIV-1, HCV, nirmatrelvir (paxlovid), have completed human phase 3 clinical Ebola virus, and Zika virus, has taught us that every new trials and have been approved (Table 2). Molnupiravir, a cytidine emerging virus has a distinct life style and a pathogenic course ribonucleoside analog first developed to inhibit influenza virus that was unknown in preceding viral infections. Moreover, SARS- replication, was shown to inhibit the SARS-CoV-2 RdRp (Painter CoV-2 is likely to become a permanent, endemic virus, like et al., 2021). Molnupiravir can pair ambiguously, as cytidine the previous, recently emerged human viruses. Repurposing or uridine, with viral RNA. This pairing introduces an elevated drugs has been an appealing strategy for the rapid translation mutation load that generates non-infectious virus particles. of drugs to the clinic. However, despite the enthusiasm for Molnupiravir, promoted by Merck for SARS-CoV-2 clinics, has this strategy, it has not produced any effective treatments for the potential to be a broad-based inhibitor; it acts against a COVID-19, or any other viral disease, including those caused number of RNA viruses, including seasonal influenza virus, by recent emergent viruses, such as Zika virus and Ebola virus. MERS-CoV, and encephalitic alphaviruses, such as Venezuelan, Drug development requires time, funding, and collaboration Eastern, and Western equine encephalitis viruses. Phase 3 clinical among clinical investigators, virologists, immunologists, and trial data from Merck have shown that a 5-day course of pharmacologists. It is important to know and understand molnupiravir reduced hospitalization or mortality by ∼50%, the drug’s target, toxicity, and pharmacodynamics, in addition compared to placebo, in patients with mild or moderate COVID- to the key viral kinetic time-points and specific (or broad) 19. Nevertheless, the efficacy of molnupiravir was reduced immune phenomena. This approach may take more time, from 50 to 30% in the published peer-reviewed data of the but it could be useful for fighting SARS-CoV-2 and for former phase 3 trial (Jayk Bernal et al., 2021). Nirmatrelvir developing drugs to combat newly emerging viruses and inhibits the main SARS-CoV-2 protease (Owen et al., 2021). future pandemics. Protease inhibitors have been shown to be powerful antivirals, as demonstrated with human immunodeficiency virus type 1 AUTHOR CONTRIBUTIONS (HIV-1) and hepatitis C virus (HCV). In a phase 3 clinical trial, nirmatrelvir was combined with ritonavir, an HIV-1 protease The author confirms being the sole contributor of this work and inhibitor that prevents enzymes in the liver from breaking has approved it for publication. down the antiviral. This combination showed 89% efficacy in preventing COVID-19 hospitalization and death. Still, the FUNDING data for nirmatrelvir, generated by Pfizer, have not yet been peer-reviewed. These two promising antivirals will probably be This work was supported by the Spanish Ministry of Science and effective against SARS-CoV-2 variants of concern, because these Innovation (PID2019-103955RB-100). Frontiers in Microbiology | www.frontiersin.org 3 February 2022 | Volume 13 | Article 843587 Martinez Failing Repurposed Antivirals Against SARS-CoV-2 REFERENCES Kalil, A. C., Patterson, T. F., Mehta, A. K., Tomashek, K. M., Wolfe, C. R., Ghazaryan, V., et al. (2021). 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Copyright © 2022 Martinez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution Publisher’s Note: All claims expressed in this article are solely those or reproduction in other forums is permitted, provided the original author(s) and of the authors and do not necessarily represent those of their affiliated the copyright owner(s) are credited and that the original publication in this journal organizations, or those of the publisher, the editors and the reviewers. is cited, in accordance with accepted academic practice. No use, distribution or Any product that may be evaluated in this article, or claim that may reproduction is permitted which does not comply with these terms. Frontiers in Microbiology | www.frontiersin.org 5 February 2022 | Volume 13 | Article 843587