Histone deacetylases inhibitors as new potential drugs against Leishmania braziliensis, the main causative agent of new world tegumentary leishmaniasis.

Abstract

The protozoan parasite Leishmania braziliensis is a major causative agent of the neglected tropical diseases Cutaneous and Mucocutaneous Leishmaniases in the New World. There are no vaccines to prevent the infection and the treatment relies on few drugs that often display high toxicity and costs. Thus, chemotherapeutic alternatives are required. Histone Deacetylases (HDACs) are epigenetic enzymes involved in the control of chromatin structure. In this work, we tested an in-house library of 78 hydroxamic acid derivatives as putative inhibitors of L. braziliensis HDACs (HDACi). The compounds were evaluated in relation to the toxicity to the host cell macrophage and to the leishmanicidal effect against L. braziliensis during in vitro infection. Eight HDACi showed significant leishmanicidal effects and the top 5 compounds showed effective concentrations (EC50) in the range of 4.38 to 10.21 μM and selectivity indexes (SI) from of 6 to 21.7. Analyses by Transmission Electron Microscopy (TEM) indicated induction of apoptotic cell death of L. braziliensis amastigotes with a necrotic phenotype. An altered chromatin condensation pattern and cellular disorganization of intracellular amastigotes was also observed. A tight connection between the mitochondrion and nuclear protrusions, presumably of endoplasmic reticulum origin, was found in parasites but not in the host cell. In flow cytometry (FC) analyses, HDACi promoted parasite cell cycle arrest in the G2-M phase and no changes were found in macrophages. In addition, the direct effect of HDACi against the promastigotes showed apoptosis as the main mechanism of cell death. The FC results corroborate the TEM analyses indicating that the HDACi lead to changes in the cell cycle and induction of apoptosis of L. braziliensis. The production of nitric oxide by the infected macrophages was not altered after treatment with the top 5 compounds. Taken together, our results evidenced new HDACi as promising agents for the development of new treatments for American Tegumentary Leishmaniasis caused by L. braziliensis.

• Authors: Luciana Ângelo de Souza, Matheus Silva E Bastos, Joice de Melo Agripino, Thiago Souza Onofre, Lourdes Fanny Apaza Calla, Tino Heimburg, Ehab Ghazy, Theresa Bayer, Victor Hugo Ferraz da Silva, Paula Dutra Ribeiro, Leandro Licursi de Oliveira, Gustavo Costa Bressan, Márcia Rogéria de Almeida Lamêgo, Abelardo Silva-Júnior, Raphael de Souza Vasconcellos, Ana Márcia Suarez-Fontes, Juliana Almeida-Silva, Marcos André Vannier-Santos, Raymond Pierce, Wolfgang Sippl, Juliana Lopes Rangel Fietto
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 180 Pg. 114191 (10 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32777278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Histone Deacetylase Inhibitors
• Nitric Oxide
• Histone Deacetylases

Topics

• Animals
• Cell Survival (drug effects, physiology)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Histone Deacetylases (metabolism)
• Humans
• Leishmania braziliensis (drug effects, enzymology, ultrastructure)
• Leishmaniasis, Cutaneous (drug therapy, enzymology, pathology)
• Macrophages (drug effects, enzymology, ultrastructure)
• Mice
• Nitric Oxide (antagonists & inhibitors, metabolism)
• RAW 264.7 Cells