Structures and dynamics of peptide and peptidomimetic inhibitors bound to the NS2B-NS3 protease of the ZIKA virus

C-Terminal Extended Hexapeptides as Potent Inhibitors of the NS2B-NS3 Protease of the ZIKA Virus

“…(18). Therefore, it is necessary to design substrate competitive inhibitors to inhibit the protease activities of NS2B-NS3 protease to contain the ZIKV (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

“…Several attempts were made to design substrate competitive inhibitors to occupy the substrate-binding site of the NS2B-NS3 protease of the ZIKV. These inhibitors include (1) small molecules (19)(20)(21)(22)(23)(24)(25)(26)(27), ( 2) peptidomimetics (28)(29)(30)(31)(32)(33), and (3) peptide inhibitors (34,35). As the protease active site is surrounded by negatively charged amino acids (acidic residues), the binding of small molecule neutral inhibitors was not effective.…”

“…These inhibitors can either make a covalent bond with the catalytically important residue Ser135 of NS3 (28,29) or bind non-covalently to the protease (30). Interestingly, recently, non-covalent peptide inhibitors were shown to bind strongly with the NS2B-NS3 protease (35). Among these inhibitors, the YKKR was found to possess the highest binding free energy (35).…”

“…Interestingly, recently, non-covalent peptide inhibitors were shown to bind strongly with the NS2B-NS3 protease (35). Among these inhibitors, the YKKR was found to possess the highest binding free energy (35). It was shown that the P1 R binds to the S1 substrate site, while P2 K and P3 K bind to the S2 and S3 sites, respectively.…”

“…It was shown that the P1 R binds to the S1 substrate site, while P2 K and P3 K bind to the S2 and S3 sites, respectively. It was proposed that the heavy amino acid Y at the P4 position provides the necessary conformational rigidity to KKR to fully occupy the substratebinding site (35). However, for the Dengue virus (DENV) protease, strong preferences for both K and R were reported at the P1 position, whereas, R and K were preferred at the P2 and P3 positions, respectively (36).…”