title: Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads.
abstract: Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal. GDP-Mannose Pyrophosphorylase (GDP-MP) is a prominent therapeutic target involved in host-parasite recognition which has been described to be essential for parasite survival. In this work, we produced and purified GDP-MPs from L. mexicana (LmGDP-MP), L. donovani (LdGDP-MP), and human (hGDP-MP), and compared their enzymatic properties. From a rationale design of 100 potential inhibitors, four compounds were identified having a promising and specific inhibitory effect on parasite GDP-MP and antileishmanial activities, one of them exhibits a competitive inhibition on LdGDP-MP and belongs to the 2-substituted quinoline series.
authors.affiliation: Chimiothérapie Antiparasitaire, UMR CNRS 8076 BioCIS, Université Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France.
authors.forename: Wei
authors.initials: W
authors.lastname: Mao
authors.affiliation: Chimiothérapie Antiparasitaire, UMR CNRS 8076 BioCIS, Université Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Daligaux
authors.affiliation: Institut de Biologie Intégrative de la Cellule, UMR 9198, CNRS, Université Paris-Sud, Université Paris-Saclay, Bâtiment 430, Orsay, 91405, France.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Lazar
authors.affiliation: Molécules Fluorées et Chimie Médicinale, UMR CNRS 8076 BioCIS, Université Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France.
authors.forename: Tâp
authors.initials: T
authors.lastname: Ha-Duong
authors.affiliation: Chimiothérapie Antiparasitaire, UMR CNRS 8076 BioCIS, Université Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0003-0050-6477
authors.initials: C
authors.lastname: Cavé
authors.affiliation: Institut de Biologie Intégrative de la Cellule, UMR 9198, CNRS, Université Paris-Sud, Université Paris-Saclay, Bâtiment 430, Orsay, 91405, France.
authors.forename: Herman
authors.initials: H
authors.lastname: van Tilbeurgh
authors.affiliation: Chimiothérapie Antiparasitaire, UMR CNRS 8076 BioCIS, Université Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.affiliation: Chimiothérapie Antiparasitaire, UMR CNRS 8076 BioCIS, Université Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France. sebastien.pomel@u-psud.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pomel
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase