Potent Inhibitory Activities of the Adenosine Analogue Cordycepin on SARS-CoV-2 Replication

[Image: see text] Nucleoside analogues are among the most successful bioactive classes of druglike compounds in pharmaceutical chemistry as they are well-known for their numerous effective bioactivities in humans, especially as antiviral and anticancer agents. Coronavirus disease 2019 (COVID-19) is still untreatable, with its causing virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continuing to wreak havoc on the ground everywhere. This complicated international situation urged all concerned scientists, including medicinal chemists and drug discoverers, to search for a potent anti-COVID-19 drug. Cordycepin (3′-deoxyadenosine) is a known natural adenosine analogue of fungal origin, which could also be synthetically produced. This bioactive phytochemical compound is characterized by several proven strong pharmacological actions that may effectively contribute to the comprehensive treatment of COVID-19, with the antiviral activities being the leading ones. Some new studies predicted the possible inhibitory affinities of cordycepin against the principal SARS-CoV-2 protein targets (e.g., SARS-CoV-2 spike (S) protein, main protease (M(pro)) enzyme, and RNA-dependent RNA polymerase (RdRp) enzyme) based on the computational approach. Interestingly, the current research showed, for the first time, that cordycepin is able to potently inhibit the multiplication of the new resistant strains of SARS-CoV-2 with a very minute in vitro anti-SARS-CoV-2 EC(50) of about 2 μM, edging over both remdesivir and its active metabolite GS-441524. The ideal pharmacophoric features of the cordycepin molecule render it a typical inhibitor of SARS-CoV-2 replication, with its flexible structure open for most types of derivatization in the future. Briefly, the current findings further support and suggest the repurposing possibility of cordycepin against COVID-19 and greatly encourage us to confidently and rapidly begin its preclinical/clinical evaluations for the comprehensive treatment of COVID-19.