3.4.4 Nucleoside analog inhibitors
Nucleoside analogs are dNTPs or rNTPs that lack 3’-OH group resulting in chain termination. They are widely used as a treatment for HBV, HCV, HIV-1, and HSV. Compared to the other RNA viruses, the proofreading activity of RdRp by the capability of 3′ to 5′ exoribonuclease (nsp14), leads up to 20-folds increase in accuracy of replication. The inhibitors enzyme of coronavirus is highly resistant to many nucleoside analogs including fabiravir (guanine analog), ribavirin (guanosine analog) and 5-fluorouracil (pyrimidine analog) (Harrison, 2020).
Remdesivir, (adenosine analog) as a potent phosphoramidate prodrug is effective against filoviruses, pneumoviruses, and paramyxoviruses with two suggested mechanisms of action (Lo et al., 2017). One is being as nucleoside analog and the second is acting on viral RdRp. Accordingly, Peters et al evaluated the efficiency of a series of doubly flexible nucleoside analogues suggesting that compound 2 with EC50 < 10 μM was promising against HCoV-NL63 (Peters et al., 2015). The combinations of nucleotide analoges can mitigate the resistance mediated by mutations in the viral RdRp, perhaps by additive or synergistic interactions effect (Pruijssers and Denison, 2019). Despite the proofreading activity, identifying nucleoside analog inhibitors hold promise for the treatment of 2019-nCoV.