Leishmanicidal Galloylquinic Acids are Noncompetitive Inhibitors of Arginase

Lorena R F De Sousa,Maria I S Lima,João B Fernandes,Caroindes J Corrêa,Maria Fátima Das G F Da Silva Silva,Suelem D Ramalho,Mônica R Da C Iemma,Paulo C Vieira,Dulce H F De Souza

doi:10.5935/0103-5053.20140115

Lorena R F De Sousa, Maria I S Lima + Show 7 more

Open Access

https://doi.org/10.5935/0103-5053.20140115

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Abstract

Leishmanicidal galloylquinic acids were isolated from the ethyl acetate extract of Byrsonima coccolobifolia. These phenols and gallic acid showed to be a new class of potent noncompetitive inhibitors of arginase ARG (Ki ranging from 0.10 to 0.68 µmol L -1 ) from Leishmania amazonensis. Quinic acid did not exhibit significant inhibition of ARG, indicating that galloyl moiety has important features that allows the enzyme-inhibitor interactions. The significant inhibitory activity of gallic acid on ARG can be a clue to understand the immune response previously observed on L. donovani, since ARG activity is associated with the decrease of the levels of NO in Leishmania infection.

Highlights

Leishmaniasis is a deadly infectious tropical disease caused by the protozoan of the genus Leishmania, which affects more than 12 million people of broad geographical distribution.[1,2] The challenges for healthcare of leishmaniasis found on available drugs such as, high toxicity, undesirable side effects, high cost and parasite resistance, reveal an urgent problem and the need for new efficient drugs.[3,4,5]Exploring for novel therapeutic opportunities, new biochemical targets have been investigated, in particular arginase (ARG) from Leishmania amazonensis have been considered an attractive target in the search for new leishmanicidal agents
We have identified the inhibition mechanism of the quinic acid esters (3-6) and gallic acid (2) as noncompetitive and mixed inhibitors, suggesting that the inhibitory activity of ARG would not be related to the formation of aggregates
Previous study showed that gallic acid increases the expression of nitric oxide synthase and cytokine genes in Leishmania major parasitised RAW 264.7 cells, as properties to combat the infection.[56]

Summary

Introduction

Leishmaniasis is a deadly infectious tropical disease caused by the protozoan of the genus Leishmania, which affects more than 12 million people of broad geographical distribution.[1,2] The challenges for healthcare of leishmaniasis found on available drugs such as, high toxicity, undesirable side effects, high cost and parasite resistance, reveal an urgent problem and the need for new efficient drugs.[3,4,5]Exploring for novel therapeutic opportunities, new biochemical targets have been investigated, in particular arginase (ARG) from Leishmania amazonensis have been considered an attractive target in the search for new leishmanicidal agents. Gallic acid (2) and galloylquinic acids (3-6) were isolated from ethyl acetate extract from leaves and stems of B. coccolobifolia, which were identified by 1D and 2D NMR spectra, and through comparison with data previously reported.[31,32,33,34,35] Galloylquinic acids (3-6) and gallic acid (2) were potent inhibitors of ARG with high affinity.

Results

Conclusion