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

Infection with SARS-CoV-2 has resulted in COVID-19 pandemic and infected more than 5
million individuals with around 0.35 million deaths worldwide till May 2020 end. Several
efforts are on in search of therapeutic interventions, but the preferred way is drug
repurposing due to the feasibility and urgency of the situation. To select and prioritize
approved antiviral drugs and drug combinations for COVID-19, 61 antiviral drugs having
proven safety profile in humans were subjected to virtual screening for binding to three
select targets namely human angiotensin-converting enzyme receptor-2 receptor-binding
domain (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) causing
proteolytic processing of viral polyprotein slab. Targeting multiple ‘disease pathogenesis
specific proteins’ within a close network of interaction or having dependent functionality can
provide effective intervention. Ledipasvir, Daclatasvir, Elbasvir, Paritaprevir, Rilpivirine and
Indinavir were identified as candidate drugs of interest for COVID-19 based on a derived
combined activity score, pharmacokinetic and pharmacodynamic parameters. Ledipasvir and
Daclatasvir and their approved marketed combination with Sofosbuvir emerged as leading
candidate drugs/drug combinations for SARS-CoV-2. These candidates have the potential
for the antiviral activity for SARS-CoV-2 infection better than the investigational drug
Remdesivir and other antiviral drugs/drug combinations being evaluated. These
drugs/combinations merit systematic fast track preclinical and clinical evaluation for COVID-
19 management. The present work brings back attention to the potential usefulness of
approved antiviral drugs/drug combinations, commonly available with established safety
profile, currently not in focus for COVID-19. It provides a rationale based approach for the
selection of drugs with potential antiviral activity against SARS-CoV-2 highlighting the
desired properties.