Dados do Trabalho

Título

Small molecules targeting Leishmania: potential targets for chemotherapy

Introdução

American Tegumentary Leishmaniasis is a disease caused by several species of Leishmania. The challenges regarding control are due in part to increasing therapeutic failure and resistance. Currently major efforts focus on the search for new and affective therapeutic formulations, as well as effective technologies in screening to accelerate the identification of promising compound candidates. Cutaneous Leishmaniasis (CL) caused a localized ulcerated lesion to disfiguring lesions in mucosal areas. L. braziliensis can also cause disseminated leishmaniasis, a severe form of disease that frequently presents on mucosal areas of the body. Previously, we identified a collection of compounds that displayed effective antiparasitic activity against L. donovani

Objetivo (s)

To evaluate the anti-parasitic activity of these compounds and their efficacy against L. braziliensis and L. major

Material e Métodos

we employed an intracellular phenotypic screening using J774 cells and a transgenic L. braziliensis cell line expressing luciferase.

Resultados e Conclusão

The primary screening showed that 15/36 compounds reduced the parasite load by >80%, without indication of cytotoxicity to the host cell. Dose response-curves demonstrated that 11/15 compounds presented EC75 values between 1 and 5uM. We observed similar anti-parasitic activity against L. braziliensis and L. major. These compounds will be further evaluated for their efficacy in bone marrow derived macrophage infections, as well as pre-clinical models of tegumentary leishmaniasis. Conclusion: This study provides preliminary evidence that small molecules can be considered as strong candidates for the development of chemotherapeutics for leishmaniasis.

Palavras-chave

Leishmania braziliensis; Leishmania major; pyrazolopyrrolidinone; drug discovery; therapeutics; infecteus deseases

Agradecimentos

1Instituto Gonçalo Moniz, Fiocruz-Bahia, Salvador, Brazil.
2Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA.
3Center for Discovery and Innovation in Parasitic Diseases, University of California, San Diego, CA, USA
4Center for Molecular Discovery (BU-CMD), Department of Chemistry, Boston University, Boston, MA, USA
5Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais (INCT-DT), Salvador, Bahia, Brazil.
NIH NIAID, CNPq