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

Authors
  • Ângelo de Souza, Luciana1
  • Silva E Bastos, Matheus2
  • de Melo Agripino, Joice3
  • Souza Onofre, Thiago4
  • Apaza Calla, Lourdes Fanny5
  • Heimburg, Tino6
  • Ghazy, Ehab7
  • Bayer, Theresa8
  • Ferraz da Silva, Victor Hugo9
  • Dutra Ribeiro, Paula10
  • Licursi de Oliveira, Leandro11
  • Costa Bressan, Gustavo12
  • de Almeida Lamêgo, Márcia Rogéria13
  • Silva-Júnior, Abelardo14
  • de Souza Vasconcellos, Raphael15
  • Suarez-Fontes, Ana Márcia16
  • Almeida-Silva, Juliana17
  • Vannier-Santos, Marcos André18
  • Pierce, Raymond19
  • Sippl, Wolfgang20
  • And 1 more
  • 1 Departamento de Biologia Geral, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
  • 2 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
  • 3 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
  • 4 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
  • 5 Departamento de Biologia Geral, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
  • 6 Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany. Electronic address: [email protected] , (Germany)
  • 7 Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany. Electronic address: [email protected] , (Germany)
  • 8 Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany. Electronic address: [email protected] , (Germany)
  • 9 Departamento de Biologia Geral, Universidade Federal de Viçosa, Minas Gerais, Brazil. Electronic address: [email protected] , (Brazil)
  • 10 Departamento de Biologia Geral, Universidade Federal de Viçosa, Minas Gerais, Brazil. Electronic address: [email protected] , (Brazil)
  • 11 Departamento de Biologia Geral, Universidade Federal de Viçosa, Minas Gerais, Brazil. Electronic address: [email protected] , (Brazil)
  • 12 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
  • 13 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
  • 14 Departamento de Veterinária, Universidade Federal de Viçosa, Minas Gerais, Brazil. Electronic address: [email protected] , (Brazil)
  • 15 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Minas Gerais, Brazil. Electronic address: [email protected] , (Brazil)
  • 16 LITEB, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil. Electronic address: [email protected] , (Brazil)
  • 17 LITEB, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil. Electronic address: [email protected] , (Brazil)
  • 18 LITEB, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil. Electronic address: [email protected] , (Brazil)
  • 19 Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, 59000 Lille, France; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (France)
  • 20 Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Germany)
  • 21 Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Minas Gerais, Brazil; Consortium A-ParaDDisE- Anti- Parasite Drug Discovery in Epigenetics - http://a-paraddise.cebio.org. Electronic address: [email protected] , (Brazil)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Aug 07, 2020
Volume
180
Pages
114191–114191
Identifiers
DOI: 10.1016/j.bcp.2020.114191
PMID: 32777278
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020 Elsevier Inc. All rights reserved.

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