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.