In silico analysis of a therapeutic target in Leishmania infantum: the guanosine-diphospho-D-mannose pyrophosphorylase.
Leishmaniases are tropical and sub-tropical diseases for which classical drugs (i.e. antimonials) exhibit toxicity and drug resistance. Such a situation requires to find new chemical series with antileishmanial activity. This work consists in analyzing the structure of a validated target in Leishmania: the GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in glycosylation and essential for amastigote survival. By comparing both human and L. infantum GDP-MP 3D homology models, we identified (i) a common motif of amino acids that binds to the mannose moiety of the substrate and, interestingly, (ii) a motif that is specific to the catalytic site of the parasite enzyme. This motif could then be used to design compounds that specifically inhibit the leishmanial GDP-MP, without any effect on the human homolog.
Université Paris-Sud 11, UMR 8076 CNRS, Chimiothérapie Antiparasitaire, 5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
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S
Pomel
J
J
Rodrigo
F
F
Hendra
C
C
Cavé
P M
PM
Loiseau
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016384:Consensus Sequence; D004285:Dogs; D015195:Drug Design; D006031:Glycosylation; D006155:Guanosine Diphosphate Mannose / Q000737:chemistry / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects / Q000201:enzymology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D008958:Models, Molecular; D008968:Molecular Conformation; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D013045:Species Specificity
D000981:Antiprotozoal Agents; D006155:Guanosine Diphosphate Mannose; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase