Drug to genome to drug: discovery of new antiplasmodial compounds

Terence B Beghyn; Julie Charton; Florence Leroux; Guillaume Laconde; Arnaud Bourin; Paul Cos; Louis Maes; Benoit Deprez

doi:10.1021/jm1014617

Drug to genome to drug: discovery of new antiplasmodial compounds

J Med Chem. 2011 May 12;54(9):3222-40. doi: 10.1021/jm1014617. Epub 2011 Apr 19.

Authors

Terence B Beghyn¹, Julie Charton, Florence Leroux, Guillaume Laconde, Arnaud Bourin, Paul Cos, Louis Maes, Benoit Deprez

Affiliation

¹ 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.

PMID: 21504142
DOI: 10.1021/jm1014617

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antimalarials / chemical synthesis*
Antimalarials / chemistry
Antimalarials / pharmacology
Carbolines / chemical synthesis*
Carbolines / chemistry
Carbolines / pharmacology
Catalytic Domain
Cyclic AMP / metabolism
Cyclic GMP / metabolism
Diketopiperazines / chemical synthesis
Diketopiperazines / chemistry
Diketopiperazines / pharmacology
Drug Design
Drug Discovery
Genome, Human
Genome, Protozoan
Humans
Hydrolysis
Models, Molecular
Molecular Sequence Data
Parasitic Sensitivity Tests
Phosphodiesterase 5 Inhibitors / chemical synthesis*
Phosphodiesterase 5 Inhibitors / chemistry
Phosphodiesterase 5 Inhibitors / pharmacology
Phosphoric Diester Hydrolases / chemistry
Phosphoric Diester Hydrolases / genetics
Plasmodium falciparum / drug effects*
Plasmodium falciparum / growth & development
Plasmodium falciparum / metabolism
Stereoisomerism
Structure-Activity Relationship
Tadalafil

Substances

Antimalarials
Carbolines
Diketopiperazines
Phosphodiesterase 5 Inhibitors
Tadalafil
Cyclic AMP
Phosphoric Diester Hydrolases
Cyclic GMP