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Lately, nucleos(t)ide antivirals topped the scene as top options for the treatment of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Targeting the two broadly conserved SARS-CoV-2 enzymes, RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN), together using only one shot is a very successful new tactic to stop SARS-CoV-2 multiplication irrespective of the SARS-CoV-2 variant type. Herein, the current studies investigated most nucleoside analogue (NA) libraries, searching for the ideal drug candidates expectedly able to act through this double tactic. Gradual computational filtration gave rise to six different promising NAs along with their corresponding triphosphate (TP) nucleotides. The subsequent biological assessment proved for the first time that, among the six NAs, riboprine and forodesine are able to hyperpotently inhibit the replication of the Omicron strain of SARS-CoV-2 with extremely low in vitro anti-RdRp, anti-ExoN, and anti-SARS-CoV-2 EC 50 values of about 0.18, 0.28, and 0.40 μM for riboprine and about 0.20, 0.31, and 0.65 μM for forodesine, respectively, surpassing remdesivir and molnupiravir. The significant probability that both compounds may also act as prodrugs for their final TP nucleotides in vivo pushed us to examine the same activities for forodesine-TP and riboprine-TP. Both nucleotides similarly displayed very promising results, respectively, which are much better than those for the two reference TP nucleotides, GS-443902 and β-d- N  4 -hydroxycytidine 5'-TP (NHC-TP). The prior in silico data supported these biochemical findings, suggesting that riboprine and forodesine molecules and their expected active TP metabolites strongly hit the key catalytic pockets of the SARS-CoV-2 RdRp's and ExoN's main active sites. In brief, the current important results of this comprehensive study revealed the interesting repurposing potentials of, mainly, the two bioactive nucleosides forodesine and riboprine and their TP nucleotides to effectively shut down the polymerase/exoribonuclease-RNA nucleotide interactions of SARS-CoV-2 and consequently treat COVID-19 infections.

Forodesine and Riboprine Exhibit Strong Anti-SARS-CoV-2 Repurposing Potential: In Silico and In Vitro Studies