Nitrile-based peptoids as cysteine protease inhibitors

Author(s)

Alves, Luana ^[1] ; Santos, Deborah A. ^[1] ; Cendron, Rodrigo ^[1] ; Rocho, Fernanda R. ^[1] ; Matos, Thiago K. B. ^[1] ; Leitao, Andrei ^[1] ; Montanari, Carlos A. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med & Biol Chem Grp NEQUIMED, Ave Trabalhador Sancarlense, 400, BR-13566590 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry; v. 41, JUL 1 2021.
• Web of Science Citations: 0

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 alpha-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: pK(i)(Neq0409) = 6.5 and pK(i)(4a) = 5.2. respectively. A retrosynthetic matched molecular pair cliff (RMMP-cliff) analysis with a Delta pK(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 5, 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. (AU)

• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/15904-6 - Characterization of cysteine protease inhibitors with antineoplastic activity by in silico and cell-based assays coupled with chemical analyses
• Grantee: Andrei Leitão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/09961-7 - Molecular Design, Synthesis, and Trypanocidal Activity of Reversible Covalent Inhibitors of Cruzain Enzyme
• Grantee: Deborah Araujo dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral