Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

Author(s):Show less -

Cianni, Lorenzo ^{[1, 2, 3, 4]} ; Lemke, Carina ^[3] ; Gilberg, Erik ^{[2, 3]} ; Feldmann, Christian ^[2] ; Rosini, Fabiana ^[1] ; Rocho, Fernanda dos Reis ^[1] ; Ribeiro, Jean F. R. ^[1] ; Tezuka, Daiane Y. ^{[1, 5]} ; Lopes, Carla D. ^[6] ; de Albuquerque, Sergio ^[6] ; Bajorath, Juergen ^[2] ; Laufer, Stefan ^[4] ; Leitao, Andrei ^[1] ; Guetschow, Michael ^[3] ; Montanari, Carlos A. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med Chem Grp, Sao Carlos, SP - Brazil

^[2] Rhein Friedrich Wilhelm Univ Bonn, Dept Life Sci Informat, B IT, LIMES Program Unit Chem Biol & Med Chem, Bonn - Germany

^[3] Univ Bonn, Pharmaceut Inst, Pharmaceut Chem 1, Bonn - Germany

^[4] Eberhard Karls Univ Tubingen, Dept Pharmaceut Med Chem, Tubingen - Germany

^[5] Univ Sao Paulo, Ribeirao Preto Sch Pharmaceut Sci, Ribeirao Preto, SP - Brazil

^[6] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Toxicol & Bromatol Anal, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 14, n. 3 MAR 2020.
• Web of Science Citations: 5

Abstract

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1 ` subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a K-i smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 mu M, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases. Author summary Despite many achievements in identifying novel agents for the treatment of tropical and neglected diseases, further research continues to be of fundamental importance. Our research groups have been using the cruzipain cysteine protease in its recombinant form, cruzain (Cz), to identify new trypanocidal agents. Considering the possible interchangeability with other cysteine proteases, the same series of dipeptidyl nitriles was tested in Leishmania mexicana LmCPB. Other potential targets for such inhibitors are human cysteine cathepsins, which are involved in different disease states. Thus, the inhibitors were also tested against cathepsins B, L, K, and S. Our results demonstrate that appropriate structural modifications of dipeptidyl nitriles can lead to inhibition of these cysteine proteases. It was also possible to identify trypanocidal agents, equipotent to benznidazole, the current drug of choice used for the treatment of Chagas disease. (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: 17/17386-0 - Molecular design and synthesis of new cruzain inhibitors with trypanocidal activity
• Grantee: Lorenzo Cianni
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme
• Grantee: Lorenzo Cianni
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)