Novel Selective and Low-Toxic Inhibitor of LmCPB2.8 Delta CTE (CPB) One Important Cysteine Protease for Leishmania Virulence

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Moreira, Vitor Partite ; da Silva Mela, Michele Ferreira ; dos Anjos, Luana Ribeiro ; Saraiva, Leonardo Figueiredo ; Velasquez, Angela M. Arenas ; Kalaba, Predrag ; Fabisikova, Anna ; Clementino, Leandro da Costa ; Aufy, Mohammed ; Studenik, Christian ; Gajic, Natalie ; Prado-Roller, Alexander ; Magalhaes, Alvicler ; Zehl, Martin ; Figueiredo, Ingrid Delbone ; Baviera, Amanda Martins ; Cilli, Eduardo Maffud ; Graminha, Marcia A. S. ; Lubec, Gert ; Gonzalez, Eduardo R. Perez

• Document type: Journal article
• Source: BIOMOLECULES; v. 12, n. 12, p. 21-pg., 2022-12-01.

Abstract

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N'-benzyl-N ''-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8 Delta CTE (CPB) with similar to 73% inhibition and an IC50-CPB of 6.0 mu M. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug. (AU)

• FAPESP's process: 18/00581-7 - SYNTHESIS AND CHARACTERIZATION OF ORGANIC COMPOUNDS WITH POTENTIAL AS NEW DRUGS AGAINST TO CHANNEL IONICOS DYSFUNCTIONS, LEISHMANIA AND ANTI-TUMOUR TREATMENT.
• Grantee: Eduardo Rene Perez Gonzalez
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/04415-4 - Therapeutics for leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new antileishmanial molecules
• Grantee: Marcia Aparecida Silva Graminha
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/19289-9 - Characterization of Mechanism of cell death potentially induced by a binuclear antileishmanial cyclopalladated CP2: a contribution to the rational drug development
• Grantee: Angela Maria Arenas Velásquez
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/03552-5 - Leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new bioactive molecules
• Grantee: Marcia Aparecida Silva Graminha
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/23015-7 - Antimicrobial photodynamic therapy by continuous and switched mode irradiation against Enterococcus faecalis and Cutibacterium acnes
• Grantee: Carla Raquel Fontana
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/02595-8 - Structural and biological characterization of synthetic Guanidines as potential agents against cutaneous and visceral Leishmaniasis
• Grantee: Eduardo Rene Perez Gonzalez
• Support Opportunities: Regular Research Grants