Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?

Author(s)

Cianni, Lorenzo ^{[1, 2, 3]} ; Feldmann, Christian Wolfgang ^[1] ; Gilberg, Erik ^{[1, 2]} ; Guetschow, Michael ^[2] ; Juliano, Luiz ^{[4, 5]} ; Leitao, Andrei ^[3] ; Bajorath, Juergen ^[1] ; Montanari, Carlos A. ^[3]

Affiliation

^[1] Rhein Friedrich Wilhelms Univ, LIMES Program Unit Chem Biol & Med Chem, B IT, Dept Life Sci Informat, Endenicher Allee 19C, D-53115 Bonn - Germany

^[2] Univ Bonn, Pharmaceut Chem 1, Pharmaceut Inst, Immenburg 4, D-53121 Bonn - Germany

^[3] Univ Sao Paulo, Inst Chem Sao Carlos, Med Chem Grp, Ave Trabalhador Sancarlense 400, BR-23566590 Sao Carlos, SP - Brazil

^[4] Univ Fed Sao Paulo, AC Camargo Canc Ctr, Rua Prof Antonio Prudente 211, BR-01509010 Sao Paulo, SP - Brazil

^[5] Univ Fed Sao Paulo, Sao Paulo Med Sch, Rua Prof Antonio Prudente 211, BR-01509010 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 62, n. 23, p. 10497-10525, DEC 12 2019.
• Web of Science Citations: 1

Abstract

Cysteine proteases are important targets for the discovery of novel therapeutics for many human diseases. From parasitic diseases to cancer, cysteine proteases follow a common mechanism, the formation of an encounter complex with subsequent nucleophilic reactivity of the catalytic cysteine thiol group toward the carbonyl carbon of a peptide bond or an electrophilic group of an inhibitor. Modulation of target enzymes occurs preferably by covalent modification, which imposes challenges in balancing cross-reactivity and selectivity. Given the resurgence of irreversible covalent inhibitors, can they impair off-target effects or are reversible covalent inhibitors a better route to selectivity? This Perspective addresses how small molecule inhibitors may achieve selectivity for different cathepsins, cruzain, rhodesain, and falcipain-2. We discuss target- and ligand-based designs emphasizing repurposing inhibitors from one cysteine protease to others. (AU)

• FAPESP's process: 16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme
• Grantee: Lorenzo Cianni
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support type: Research Projects - Thematic Grants