Nitrile-based peptoids as cysteine protease inhibitors. (1st July 2021)

• Record Type: Journal Article
• Authors: Alves, Luana; Santos, Deborah A.; Cendron, Rodrigo; Rocho, Fernanda R.; Matos, Thiago K.B.; Leitão, Andrei; Montanari, Carlos A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 41(2021)
• Publication Date: 2021-07-01
• Subjects: Peptoids -- Nitrile warhead -- Cysteine protease inhibitors -- Biochemical kinetic assays -- Docking; Cat cathepsin -- CP cysteine protease -- DPN dipeptidyl nitrile -- MMP matched molecular pair -- SAR structure-activity relationship; 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.2021.116211
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Peptidomimetics of the class of dipeptidyl nitrile analog peptoids were synthesized as inhibitors of mammalian cysteine proteases of the papain superfamily. The dipeptidyl nitrile side chains were attached to the peptide backbone's nitrogen atom, not to the α-carbons. Synthesized nitrile-based peptoid analogs that lack the hydrogen amide at P2-P3 are responsible for many of the secondary structure elements in peptides and proteins, making them resistant to proteolysis. The designed peptoids would lose a hydrogen bond with cruzain Asp161 decreasing the affinity toward the enzyme. A structure-activity relationship and matched molecular pair-based analysis between the dipeptidyl nitrile Neq0409 and its peptoid 4a yielded the following cruzain affinities: p K i Neq0409 = 6.5 and p K i 4a = 5.2. respectively. A retrosynthetic matched molecular pair cliff (RMMP-cliff) analysis with a Δp K i Neq0409- 4a of 1.3 log is found for this transformation. These novel peptoids were then optimized, leading to compound 4i, with high cruzain inhibition (pKi = 6.8). Cross-class cathepsin activity was observed for some of these novel compounds against cathepsins K, L and S, while other compounds presented a selective inhibition of cathepsin K (4b, 4c, 4k ) over ten times higher than the other enzymes. The putative mode of binding was determined by using covalent docking, which also aided to describe the structure-activity relationship (SAR). Interestingly, none of the peptoids inhibited CatB to any appreciable extent. These results provide guidance to identify novel bioactive nitrile-based peptoids.