Therapeutics for leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new antileishmanial molecules

• Grant number: 20/04415-4
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2021
• End date: October 31, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Marcia Aparecida Silva Graminha
• Grantee: Marcia Aparecida Silva Graminha
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Andrew Philip Thomas
• Associated scholarship(s): 22/04596-4 - Therapeutics for leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new antileishmanial molecules, BP.TT

Abstract

Leishmaniasis is a pathogenic disease found throughout the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance to them makes providing new therapeutic alternatives urgent. We have been studying a new furoxan molecule, 14e, which present efficacy in diminish the parasite load in L. infantum infected hamsters. The parasitemia reduction might be related to inhibition of a parasitic protease, the cysteine protease B, release of NO and interference in the parasite Ca2+ homeostasis. Although we did not observe neither side effects nor elevation of hepatic/ renal biomarkers in the plasma levels, 14e presented low solubility, which turns difficult its use in a possible oral administration. Thus, rational chemical modifications has been made in order to change its solubility and keep its capacity to inhibit CPB, an important virulence factor of Leishmania. These data strength our already existent collaboration with the groups LAPDESF from FCF-UNESP and calcium signaling from Rutgers University in order to advance in the comprehension of the antileishmanial properties of the new synthetic derivatives as well as to evaluate their NO-donor potential and protease inhibition. Moreover, another goal of this project is to continue our screening program to search for new antileishmanial agents from natural sources or synthetic molecules, including other research groups to our collaboration network. This proposal is multidisciplinar and bears different areas including molecular genetics and biochemistry, relying on the efforts of students and researchers and allowing exchange of personnel among these groups. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

VELASQUEZ, ANGELA M. A.; BARTLETT, PAULA J.; LINARES, IRWIN A. P.; PASSALACQUA, THAIS G.; TEODORO, DAPHNE D. L.; IMAMURA, KELY B.; VIRGILIO, STELA; TOSI, LUIZ R. O.; LEITE, ALINE DE LIMA; BUZALAF, MARILIA A. R.; et al. ew Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Deat. Antimicrobial Agents and Chemotherapy, v. 66, n. 1, JAN 2022. (16/18191-5, 16/05345-4, 18/23015-7, 20/04415-4, 17/03552-5, 16/19289-9, 19/21661-1)

LINARES, IRWIN A. P.; URIA, MARICELY SANCHEZ; GRAMINHA, MARCIA A. S.; IGLESIAS, BERNARDO ALMEIDA; VELASQUEZ, ANGELA M. A.. Antileishmanial activity of tetra-cationic porphyrins with peripheral Pt(II) and Pd(II) complexes mediated by photodynamic therapy. Photodiagnosis and Photodynamic Therapy, v. 42, p. 10-pg., 2023-06-13. (18/23015-7, 20/04415-4, 16/19289-9)

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; et al. Novel Selective and Low-Toxic Inhibitor of LmCPB2.8 Delta CTE (CPB) One Important Cysteine Protease for Leishmania Virulence. BIOMOLECULES, v. 12, n. 12, p. 21-pg., 2022-12-01. (18/00581-7, 20/04415-4, 16/19289-9, 17/03552-5, 18/23015-7, 21/02595-8)