Structure of EV71 3Cpro in complex with NK-1.8k: Indications for the development of anti-enterovirus protease inhibitor [PublishAheadOfPrint]

Hand-foot-and-mouth disease (HFMD) caused by enterovirus is a threat to public health in worldwide. Up-to-date, enterovirus 71 (EV71) becomes one of the major causative agents of HFMD in Pacific-Asia region and causes millions of infections from its outbreak. However, no drug is currently available for clinical therapeutics. In our previous works, we developed a set of protease inhibitors (PIs) targeting EV71 3C^pro, among which NK-1.8k and NK-1.9k with various active group have high potency and selectivity. Here we determine the structures of PI NK-1.8k in complex with wild-type (WT) and drug-resistant EV71 3C^pro. Comparison with unliganded EV71 3C^pro and its complex with AG7088, these structures indicated the mutation of N69 to a serine residue destabilized S2 pocket. Thus the mutation influenced the cleavage activity of EV71 3C^pro and the inhibitory activity of NK-1.8k in vitro protease assay and highlighted Site-69 as an additional key site for PI design. More information for the optimization of P1' -P4 groups of PI are also obtained from these structures. Together with our previous works, these results in-depth elucidate inhibitory mechanism of PIs and shed the light to develop clinically-used PIs to treat the infections of EV71 and other enteroviruses.

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