SAR evolution towards potent C-terminal carboxamide peptide inhibitors of Zika virus NS2B-NS3 protease. (1st March 2022)

• Record Type: Journal Article
• 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.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 57(2022)
• Publication Date: 2022-03-01
• Subjects: ZIKV -- NS2B-NS3 protease -- Peptide inhibitors -- Peptidomimetic inhibitors -- Non-covalent inhibitors -- Benzylamides; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116631
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 P 1, P 2, P 3 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 P 1 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).