Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases

Author(s)

Cianni, Lorenzo ^[1] ; Rocho, Fernanda dos Reis ^[1] ; Rosini, Fabiana ^[1] ; Bonatto, Vinicius ^[1] ; Ribeiro, Jean F. R. ^[1] ; Lameira, Jeronimo ^[1] ; Leitao, Andrei ^[1] ; Shamim, Anwar ^[1] ; Montanari, Carlos A. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med & Biol Chem Grp, Ave Trabalhador Sancarlense 400, BR-23566590 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: BIOORGANIC CHEMISTRY; v. 101, AUG 2020.
• Web of Science Citations: 1

Abstract

Cysteine proteases (CPs) are involved in a myriad of actions that include not only protein degradation, but also play an essential biological role in infectious and systemic diseases such as cancer. CPs also act as biomarkers and can be reached by active-based probes for diagnostic and mechanistic purposes that are critical in health and disease. In this paper, we present the modulation of a CP panel of parasites and mammals (Trypanosoma cruzi cruzain, LmCPB, CatK, CatL and CatS), whose inhibition by nitrile peptidomimetics allowed the identification of specificity and selectivity for a given CP. The activity cliffs identified at the CP inhibition level are useful for retrieving trends through multiple structure-activity relationships. For two of the cruzain inhibitors (10g and 4e), both enthalpy and entropy are favourable to Gibbs binding energy, thus overcoming enthalpy-entropy compensation (EEC). Group contribution of individual molecular modification through changes in enthalpy and entropy results in a separate partition on the relative differences of Gibbs binding energy (Delta Delta G). Overall, this study highlights the role of CPs in polypharmacology and multi-target screening, which represents an imperative trend in the actual drug discovery effort. (AU)

• 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
• 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: 18/03985-1 - Molecular design, synthesis, and trypanocidal activity of reversible covalent inhibitors of cruzain enzyme
• Grantee: Anwar Shamim
• Support type: Scholarships in Brazil - Post-Doctorate