4. Expert opinion
In this review, the inhibitors against 3Cpro are summarized and the structural basis of inhibition specificities of 3Cpro and 3CLpro
by peptidomimetic compounds described. The tripeptide aldehyde and the
tripeptides with the α,β-unsaturated group as Michael acceptor (e.g.,
AG7088) for the active-site Cys are the potent inhibitors of 3Cpro. AG7088 has been shown to be effective in inhibiting many 3Cpro from a broad spectrum of picornavirus, but failed to inhibit SARS-CoV 3CLpro. The AG7088 analogues with P2 cyclohexyl moiety and additional P3 t-butyl group favor the binding with the 3CLpro. Crystal structures can be used to elucidate the subtle changes between the active-site structures of 3Cpro and 3CLpro [73-77]. The separate efforts of developing inhibitors against 3Cpro [78] and 3CLpro [79-81]
may be merged to provide the rationale to design selective potent
inhibitors against each type of the proteases, that is, with suitable
modifications, the inhibitors of 3CLpro can be converted into the inhibitors of 3Cpro and vice versa. Moreover, a group of compounds were found to inhibit 3Cpro and 3CLpro
almost equally, providing a possibility of developing dual inhibitors
against both proteases. These exciting discoveries will lead to more
varieties of inhibitors, which can then be potentially used to treat the
diseases caused by picornavirus and CoV.
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