Dados do Trabalho

Título

ANTILEISHMANIAL ACTIVITY OF ACYCLIC PHOSPHONATE NUCLEOSIDES IN LEISHMANIA INFANTUM

Introdução

Visceral leishmaniasis (VL), caused by Leishmania infantum, is a fatal neglected tropical disease in South America. Current treatments are restricted and have severe side effects, leading to treatment abandonment and resistance. There is an urgent need to identify and develop new drugs. Acyclic nucleoside phosphonates (ANPs), nucleotide analogues, are the cornerstone of antiviral therapy. In previous studies, we identified their potential antileishmanial activity.

Objetivo (s)

To investigate the in vitro antileishmanial activity of ANPs compounds against L. infantum and cellular alterations induced by the treatment.

Material e Métodos

Antileishmanial activity against promastigote and amastigote forms of L. infantum and cytotoxic in mammalian cells (NCTC L-929) of the ANPS compounds were determined, using phenotypic assays. Promastigotes and NCTC cells were incubated with compounds for different periods, and the cell viability was verified by colorimetric assay using the MTT reagent. Peritoneal macrophages were infected with isolated amastigotes and incubated with compounds. Thus, the cells were fixed, stained with Giemsa and counted using an optical microscope, to determine the infection index. The Selectivity Index (SI) of these compounds was also calculated by the ratio of cytotoxicity and amastigote activity (CEUA/IAL nº 5/2021).

Resultados e Conclusão

RESULTS: Among 25 compounds analyzed, 11 of them demonstrated anti-promastigote activity, exhibiting 50% Effective Concentration (EC50) values ranging from 9.29 to 97.37 μM. As for the amastigote activity, four compounds exhibit the values of EC50 range from 8.02 to 31.95 μM. Six compounds showed no cytotoxicity at the highest concentration (> 200 µM). The SI ranging from 0.4 to 4.2. The most active compound in both forms of the parasite was subjected to mechanism of action assays to analyze cellular alterations. CONCLUSION: While the utilization of ANPs is well established in viral therapies, in vitro investigations have suggested their potential antileishmanial activity, further explorations into their mechanisms of action at the cellular and molecular level in future studies can be a valuable contribution to the search of new treatments for leishmaniasis.  

Palavras Chave

Leishmania infantum; acyclic phosphonate nucleosides; antileishmanial activity; phenotypic assays.