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.
Highlights
Leishmaniases are vector-borne neglected tropical diseases caused by a protozoan parasite from the genus Leishmania and transmitted by hematophagous female phlebotomine sandflies
A knockout of the gene encoding for GDP-Mannose Pyrophosphorylase (GDP-MP) in L. mexicana lead to an absence of development in the macrophage in vitro and to an absence of parasite persistence in vivo (Garami and Ilg, 2001; Stewart et al, 2005). These results show that GDP-MP is critical for amastigote survival and is an interesting drug therapeutic target to be exploited for antileishmanial drug development
A docking study of the identified competitive inhibitors on GDP-MP structural models showed that compound A binds to both LdGDP-MP and hGDP-MP with similar potency and binding modes: the quinoline, piperazine, and tert-butyl groups occupying the same position as the GDP-mannose nucleotide, ribose and mannose moieties, respectively, in both catalytic sites (Daligaux et al, 2016a; Figure 1C)
Summary
Leishmaniases are vector-borne neglected tropical diseases caused by a protozoan parasite from the genus Leishmania and transmitted by hematophagous female phlebotomine sandflies. The chemical approach to design leishmanial GDP-MP inhibitors relied on the pharmacomodulation of the GDPmannose from the analysis of enzyme molecular models, by substituting for example the mannose moiety by a phenyl group, the pyrophosphate by a triazole or a phosphonate, the ribose by an ether oxide group or a deoxyribose and the guanine by different heterocycles such as purine analogs or quinolines, especially two-substituted quinolines which have been previously described to display promising in vitro and in vivo antileishmanial activities (Fournet et al, 1993, 1994, 1996; Nakayama et al, 2005, 2007; Campos-Vieira et al, 2008; Loiseau et al, 2011). The presence of two-substituted quinolines in these compounds designed could potentiate their antileishmanial activities through GDP-MP inhibition
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