Leishmania infantum arginase: biochemical characterization and inhibition by naturally occurring phenolic substances

Andreza R Garcia; Danielle M P Oliveira; Ana Claudia F Amaral; Jéssica B Jesus; Ana Carolina Rennó Sodero; Alessandra M T Souza; Claudiu T Supuran; Alane B Vermelho; Igor A Rodrigues; Anderson S Pinheiro

doi:10.1080/14756366.2019.1616182

Leishmania infantum arginase: biochemical characterization and inhibition by naturally occurring phenolic substances

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1100-1109. doi: 10.1080/14756366.2019.1616182.

Affiliations

¹ a Graduate Program in Pharmaceutical Sciences , School of Pharmacy, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil.
² b Department of Biochemistry , Institute of Chemistry, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil.
³ c Department of Natural Products , Farmanguinhos, FIOCRUZ , Rio de Janeiro , Brazil.
⁴ d Department of Drugs and Medicines , School of Pharmacy, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil.
⁵ e Neurofarba Department , Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche , Florence , Italy.
⁶ f Department of General Microbiology , Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil.
⁷ g Department of Natural Products and Food , School of Pharmacy, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil.

Abstract

Inhibition of Leishmania arginase leads to a decrease in parasite growth and infectivity and thus represents an attractive therapeutic strategy. We evaluated the inhibitory potential of selected naturally occurring phenolic substances on Leishmania infantum arginase (ARGLi) and investigated their antileishmanial activity in vivo. ARGLi exhibited a V_max of 0.28 ± 0.016 mM/min and a K_m of 5.1 ± 1.1 mM for L-arginine. The phenylpropanoids rosmarinic acid and caffeic acid (100 µM) showed percentages of inhibition of 71.48 ± 0.85% and 56.98 ± 5.51%, respectively. Moreover, rosmarinic acid and caffeic acid displayed the greatest effects against L. infantum with IC₅₀ values of 57.3 ± 2.65 and 60.8 ± 11 μM for promastigotes, and 7.9 ± 1.7 and 21.9 ± 5.0 µM for intracellular amastigotes, respectively. Only caffeic acid significantly increased nitric oxide production by infected macrophages. Altogether, our results broaden the current spectrum of known arginase inhibitors and revealed promising drug candidates for the therapy of visceral leishmaniasis.

Keywords: arginase; caffeic acid; inhibitor; rosmarinic acid; visceral leishmaniasis.

MeSH terms

Animals
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / pharmacology*
Arginase / antagonists & inhibitors*
Arginase / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Leishmania infantum / drug effects*
Leishmania infantum / enzymology
Leishmania infantum / growth & development
Macrophages / drug effects
Macrophages / parasitology
Mice
Mice, Inbred BALB C
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
Phenols / chemistry
Phenols / pharmacology*
RAW 264.7 Cells
Structure-Activity Relationship

Substances

Antiprotozoal Agents
Enzyme Inhibitors
Phenols
Arginase

Grants and funding

This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional Cientıfico e Tecnologico (CNPq) and PROEP/CNPq 407856/17, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and by a Brazil Initiative Collaboration Grant from Brown University. ARG is recipient of a Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) graduate fellowship.