Stefania Colarusso, Federica Ferrigno, Simona Ponzi, Francesca Pavone, Immacolata Conte, Luigi Abate, Elisa Beghetto, Antonino Missineo, Jerome Amaudrut, Alberto Bresciani, Giacomo Paonessa, Licia Tomei, Christian Montalbetti, Elisabetta Bianchi, Carlo Toniatti, Jesus M. Ontoria, SAR evolution towards potent C-terminal carboxamide peptide inhibitors of Zika virus NS2B-NS3 protease, Bioorganic & Medicinal Chemistry, Volume 57, 2022, 116631, ISSN 0968-0896, https://doi.org/10.1016/j.bmc.2022.116631.
Zika virus (ZIKV), a member of the Flaviviridae family, is known to cause severe neurological disorders and congenital malformations. The NS2B-NS3 serine protease, a critical enzyme for viral replication, represents a highly promising target for the development of novel antiviral agents against ZIKV.
In this study, we conducted a structure-activity relationship (SAR) analysis of a series of substrate-like linear tripeptides designed to inhibit the NS2B-NS3 protease through a non-covalent mechanism. By systematically optimizing the P1, P2, and P3 positions, as well as the N-terminal and C-terminal regions of the tripeptides, we identified potent inhibitors with sub-micromolar activity. Key structural advancements included the incorporation of phenylglycine as an arginine-mimicking group at the P1 position and benzylamide as the C-terminal fragment.
Further refinement of the SAR led to a new series of peptides featuring 4-substituted phenylglycine at the P1 position. These optimized compounds demonstrated high potency, achieving double-digit nanomolar inhibition of the Zika protease (IC50 = 30 nM), along with excellent selectivity against trypsin-like proteases and proteases from other flaviviruses, such as Dengue 2 virus (DEN2V) and West Nile virus (WNV).
This work highlights the potential of tailored peptide-based inhibitors for the development of targeted antiviral therapies against Zika virus, paving the way for future therapeutic advances.