Comprehensive Consensus Analysis of SARS-CoV-2 Drug Repurposing Campaigns

Abstract

The current COVID-19 pandemic has elicited extensive repurposing efforts (both small and large scale) to rapidly identify COVID-19 treatments among approved drugs. Herein, we provide a literature review of large-scale SARS-CoV-2 antiviral drug repurposing efforts and highlight a marked lack of consistent potency reporting. This variability indicates the importance of standardizing best practices—including the use of relevant cell lines, viral isolates, and validated screening protocols. We further surveyed available biochemical and virtual screening studies against SARS-CoV-2 targets (Spike, ACE2, RdRp, PL pro , and M pro ) and discuss repurposing candidates exhibiting consistent activity across diverse, triaging assays and predictive models. Moreover, we examine repurposed drugs and their efficacy against COVID-19 and the outcomes of representative repurposed drugs in clinical trials. Finally, we propose a drug repurposing pipeline to encourage the implementation of standard methods to fast-track the discovery of candidates and to ensure reproducible results.

Potential Inhibitors Targeting Papain-Like Protease of SARS-CoV-2: Two Birds With One Stone

“…Drug repurposing refers to the discovery of new therapeutic uses of clinically available drugs. It is a prompt strategy in searching of medications for COVID-19 therapy since the traditional drug discovery process can be costly and takes decades to complete ( Aherfi et al, 2021 ; Hijikata et al, 2021 ; Mslati et al, 2021 ; Shende et al, 2021 ). As repurposed drugs have gone through clinical trial, important parameters of these drugs, such as inhibitory potential, cell permeability, bio-availability, and safety, have been well characterized and can be available in a short time in face of pandemics ( Pushpakom et al, 2019 ).…”

Best practices for repurposing studies

“…This is unfavourable to the application of free energy perturbation strategies to evaluate dissimilar chemotypes. In summary, the best path forward is to measure the affinity of the proposed compounds using best practices [25], and then make a comparison to the requirements of PK/PD for the target. In this way one can determine better the mode of action, and relate this to any phenotypic observations.…”

Antivirales (a excepción del virus de la inmunodeficiencia humana y la hepatitis)

“…Esta vía de desarrollo se ve reflejada en la utilización contra algunas infecciones virales del imiquimod, un agonista de los receptores tipo Toll (TLR) y estimulador inespecífico de la respuesta inmunitaria, así como de los interferones, mediadores de la inmunidad innata e inductores de muchas proteínas celulares de resistencia a la infección. Esta estrategia también se emplea en los estudios dirigidos a redireccionar en terapéutica antiviral moléculas ya utilizadas contra otros agentes infecciosos o en enfermedades inflamatorias [39] , [40] . De este modo, la COVID-19 ha estimulado los estudios de todo tipo sobre fármacos como la hidroxicloroquina, la ivermectina, la colchicina, el tocilizumab (anticuerpo monoclonal que bloquea los receptores de la interleucina-6), el baricitinib y el tofacitinib (inhibidores de cinasas Janus) [39] , [40] , [41] .…”

“…Esta estrategia también se emplea en los estudios dirigidos a redireccionar en terapéutica antiviral moléculas ya utilizadas contra otros agentes infecciosos o en enfermedades inflamatorias [39] , [40] . De este modo, la COVID-19 ha estimulado los estudios de todo tipo sobre fármacos como la hidroxicloroquina, la ivermectina, la colchicina, el tocilizumab (anticuerpo monoclonal que bloquea los receptores de la interleucina-6), el baricitinib y el tofacitinib (inhibidores de cinasas Janus) [39] , [40] , [41] . Sin embargo, hay que recordar que, por el momento, los antivirales más eficaces son muy específicos de sus dianas virales, una propiedad que corresponde poco al proceso de reorientación de fármacos utilizados en otras indicaciones.…”