GDP-Mannose Pyrophosphorylase: A Biologically Validated Target for Drug Development Against Leishmaniasis

Abstract

Leishmaniases are neglected tropical diseases that threaten about 350 million people in 98 countries around the world. In order to find new antileishmanial drugs, an original approach consists in reducing the pathogenic effect of the parasite by impairing the glycoconjugate biosynthesis, necessary for parasite recognition and internalization by the macrophage. Some proteins appear to be critical in this way, and one of them, the GDP-Mannose Pyrophosphorylase (GDP-MP), is an attractive target for the design of specific inhibitors as it is essential for Leishmania survival and it presents significant differences with the host counterpart. Two GDP-MP inhibitors, compounds A and B, have been identified in two distinct studies by high throughput screening and by a rational approach based on molecular modeling, respectively. Compound B was found to be the most promising as it exhibited specific competitive inhibition of leishmanial GDP-MP and antileishmanial activities at the micromolar range with interesting selectivity indexes, as opposed to compound A. Therefore, compound B can be used as a pharmacological tool for the development of new specific antileishmanial drugs.

Keywords: GDP-mannose pyrophosphorylase; Leishmania; drug development; inhibitors; therapeutic target.

Figure 1

Mannose activation pathways and GDP-MP inhibitors. (A) Mannose activation pathways and glycoconjugate biosynthesis in Leishmania. The GDP-MP substrates and products are indicated in blue. The GDP-MP is circled in red. (B) Chemical structures of compounds A,B. (C) Docking analyses of compound A (top) and B (bottom) in LdGDP-MP (left) and hGDP-MP (right) catalytic sites. The protein surface is colored as a function of the charge density: red, white, and blue colors indicating negative, neutral, and positive area, respectively. Magnesium ion is represented by a green sphere. The amino acids that make contact with compound A,B in the catalytic sites are indicated in their one-letter code and number in the sequence (Adapted from Daligaux et al., ; Mao et al., 2017).