SAR evolution towards potent C-terminal carboxamide peptide inhibitors of Zika virus NS2B-NS3 protease

• Published in: Bioorganic & medicinal chemistry 2022-03, Vol.57, p.116631-116631, Article 116631
• Main Authors: Colarusso, Stefania, Ferrigno, Federica, Ponzi, Simona, Pavone, Francesca, Conte, Immacolata, Abate, Luigi, Beghetto, Elisa, Missineo, Antonino, Amaudrut, Jerome, Bresciani, Alberto, Paonessa, Giacomo, Tomei, Licia, Montalbetti, Christian, Bianchi, Elisabetta, Toniatti, Carlo, Ontoria, Jesus M.
• Format: Article
• Language: English
• Subjects: Benzylamides; Non-covalent inhibitors; NS2B-NS3 protease; Peptide inhibitors; Peptidomimetic inhibitors; ZIKV
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.116631

[Display omitted] Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations. The NS2B-NS3 viral serine protease is an attractive target for the development of new antiviral agents against ZIKV. We report here a SAR study on a series of substrate-like linear tripeptides that inhibit in a non-covalent manner the NS2B-NS3 protease. Optimization of the residues at positions P1, P2, P3 and of the N-terminal and C-terminal portions of the tripeptide allowed the identification of inhibitors with sub-micromolar potency with phenylglycine as arginine-mimicking group and benzylamide as C-terminal fragment. Further SAR exploration and application of these structural changes to a series of peptides having a 4-substituted phenylglycine residue at the P1 position led to potent compounds showing double digit nanomolar inhibition of the Zika protease (IC50 = 30 nM) with high selectivity against trypsin-like proteases and the proteases of other flavivirus, such as Dengue 2 virus (DEN2V) and West Nile virus (WNV).