title: Drug to genome to drug: discovery of new antiplasmodial compounds.
abstract: The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum . However, it appears that screening directly on the parasite is a more rewarding approach. The "drug to genome to drug" approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum.
authors.affiliation: INSERM U761 Biostructures and Drug Discovery, Faculté de Pharmacie, Université Lille Nord de France, Institut Pasteur de Lille, and Pôle de Recherche Interdisciplinaire pour le Médicament , Lille F-59000, France.
authors.forename: Terence B
authors.initials: TB
authors.lastname: Beghyn
authors.forename: Julie
authors.initials: J
authors.lastname: Charton
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Guillaume
authors.initials: G
authors.lastname: Laconde
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourin
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D055808:Drug Discovery; D015894:Genome, Human; D018503:Genome, Protozoan; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D021261:Parasitic Sensitivity Tests; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000068581:Tadalafil
chemical_list: D000962:Antimalarials; D002243:Carbolines; D054659:Diketopiperazines; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP