title: Discovery of Potent Inhibitors of Schistosoma mansoni NAD⁺ Catabolizing Enzyme.
abstract: The blood fluke Schistosoma mansoni is the causative agent of the intestinal form of schistosomiasis (or bilharzia). Emergence of Schistosoma mansoni with reduced sensitivity to praziquantel, the drug currently used to treat this neglected disease, has underlined the need for development of new strategies to control schistosomiasis. Our ability to screen drug libraries for antischistosomal compounds has been hampered by the lack of validated S. mansoni targets. In the present work, we describe a virtual screening approach to identify inhibitors of S. mansoni NAD(+) catabolizing enzyme (SmNACE), a receptor enzyme suspected to be involved in immune evasion by the parasite at the adult stage. Docking of commercial libraries into a homology model of the enzyme has led to the discovery of two in vitro micromolar inhibitors. Further structure-activity relationship studies have allowed a 3-log gain in potency, accompanied by a largely enhanced selectivity for the parasitic enzyme over the human homologue CD38.
authors: †Laboratoire des Systèmes Chimiques Fonctionnels, MEDALIS Drug Discovery Center, Faculté de Pharmacie, CAMB UMR7199 CNRS/Université de Strasbourg, 67401 Illkirch, France.|‡Laboratoire d'Innovation Thérapeutique, MEDALIS Drug Discovery Center, Faculté de Pharmacie, LIT UMR7200 CNRS/Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France.
authors: Sylvain A
authors: SA
authors: Jacques
authors: †Laboratoire des Systèmes Chimiques Fonctionnels, MEDALIS Drug Discovery Center, Faculté de Pharmacie, CAMB UMR7199 CNRS/Université de Strasbourg, 67401 Illkirch, France.
authors: Isabelle
authors: I
authors: Kuhn
authors: †Laboratoire des Systèmes Chimiques Fonctionnels, MEDALIS Drug Discovery Center, Faculté de Pharmacie, CAMB UMR7199 CNRS/Université de Strasbourg, 67401 Illkirch, France.
authors: Oleksandr
authors: O
authors: Koniev
authors: †Laboratoire des Systèmes Chimiques Fonctionnels, MEDALIS Drug Discovery Center, Faculté de Pharmacie, CAMB UMR7199 CNRS/Université de Strasbourg, 67401 Illkirch, France.
authors: Francis
authors: F
authors: Schuber
authors: §Department of Microbiology, University of Alabama at Birmingham, 276 BBRB Box 11, 1720 Second Avenue South, Birmingham Alabama 35294, United States.
authors: Frances E
authors: FE
authors: Lund
authors: †Laboratoire des Systèmes Chimiques Fonctionnels, MEDALIS Drug Discovery Center, Faculté de Pharmacie, CAMB UMR7199 CNRS/Université de Strasbourg, 67401 Illkirch, France.
authors: Alain
authors: A
authors: Wagner
authors: †Laboratoire des Systèmes Chimiques Fonctionnels, MEDALIS Drug Discovery Center, Faculté de Pharmacie, CAMB UMR7199 CNRS/Université de Strasbourg, 67401 Illkirch, France.
authors: Hélène
authors: H
authors: Muller-Steffner
authors: ‡Laboratoire d'Innovation Thérapeutique, MEDALIS Drug Discovery Center, Faculté de Pharmacie, LIT UMR7200 CNRS/Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France.
authors: Esther
authors: E
authors: Kellenberger
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009243:NAD / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000187:drug effects / Q000201:enzymology*; D012555:Schistosomiasis mansoni / Q000188:drug therapy* / Q000201:enzymology / Q000469:parasitology*; D013329:Structure-Activity Relationship
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D009243:NAD; D051997:ADP-ribosyl Cyclase 1