Rationale Based Selection and Prioritization of Antiviral Drugs for COVID-19 Management (preprint)

ABSTRACT

Infection with SARS-CoV-2 has resulted in COVID-19 pandemic and infected more than 5million individuals with around 0.35 million deaths worldwide till May 2020 end. Severalefforts are on in search of therapeutic interventions, but the preferred way is drugrepurposing due to the feasibility and urgency of the situation. To select and prioritizeapproved antiviral drugs and drug combinations for COVID-19, 61 antiviral drugs havingproven safety profile in humans were subjected to virtual screening for binding to threeselect targets namely human angiotensin-converting enzyme receptor-2 receptor-bindingdomain (hACE-2) involved in virus entry, SARS-CoV-2 RNA dependent RNA polymerase(RdRp) responsible for viral RNA replication and SARS-CoV-2 main protease (MPro) causingproteolytic processing of viral polyprotein slab. Targeting multiple ‘disease pathogenesisspecific proteins’ within a close network of interaction or having dependent functionality canprovide effective intervention. Ledipasvir, Daclatasvir, Elbasvir, Paritaprevir, Rilpivirine andIndinavir were identified as candidate drugs of interest for COVID-19 based on a derivedcombined activity score, pharmacokinetic and pharmacodynamic parameters. Ledipasvir andDaclatasvir and their approved marketed combination with Sofosbuvir emerged as leadingcandidate drugs/drug combinations for SARS-CoV-2. These candidates have the potentialfor the antiviral activity for SARS-CoV-2 infection better than the investigational drugRemdesivir and other antiviral drugs/drug combinations being evaluated. Thesedrugs/combinations merit systematic fast track preclinical and clinical evaluation for COVID-19 management. The present work brings back attention to the potential usefulness ofapproved antiviral drugs/drug combinations, commonly available with established safetyprofile, currently not in focus for COVID-19. It provides a rationale based approach for theselection of drugs with potential antiviral activity against SARS-CoV-2 highlighting thedesired properties.