title: Glycolysis and proteases as targets for the design of new anti-trypanosome drugs.
abstract: Glycolysis is considered as a promising target for new drugs against parasitic trypanosomatid protozoa, because this pathway plays an essential role in their ATP supply. Trypanosomatid glycolysis is unique in that it is compartmentalised, and many of its enzymes display specific structural and kinetic features. Structure- and catalytic mechanism-based approaches are applied to design compounds that inhibit the glycolytic enzymes of the parasites without affecting the corresponding proteins of the human host. For some trypanosomatid enzymes, potent and selective inhibitors have already been developed that affect only the growth of cultured trypanosomatids, and not mammalian cells. Examples are developed concerning all enzymes in the hexoses part with also others concerning glyceraldehyde-phosphate dehydrogenase and pyruvate-kinase for the trioses part. Concerning cysteine protease inhibitor development, a great number of irreversible alkylating agents have shown their efficacy towards the active site cysteine of parasite proteases. This includes fluoromethylketones, epoxides, diazomethylketones, vinylsulfones to mention a few. These functional groups are activated electrophiles that react with the nucleophilic cysteine of the active site and are generally quite selective for cysteine versus serine. They are thought to be also reactive to numerous other nucleophiles in the body, especially other thiols. This potentially hampering property seems not to be detrimental for two reasons: first a recent report has shown that cysteine protease inhibitors containing a vinylsulfone electrophile are unreactive towards thiols such as glutathione and can be considered to be inert in the absence of catalytic machinery. Secondly, irreversible inhibitors are shown to be less toxic than presumed in the parasite treatment, owing to some bioselectivity displayed by the parasite itself.
authors.affiliation: Groupe Chimie Organique Biologique, Laboratoire de Synth se et Physicochimie de Mol cules d Int r t Biologique, UMR-CNRS 5068, Universit  Paul Sabatier, Toulouse, France. perie@cict.fr
authors.forename: Faouzi
authors.initials: F
authors.lastname: Lakhdar-Ghazal
authors.forename: Casimir
authors.initials: C
authors.lastname: Blonski
authors.forename: Michele
authors.initials: M
authors.lastname: Willson
authors.forename: Paul
authors.initials: P
authors.lastname: Michels
authors.forename: Jacques
authors.initials: J
authors.lastname: Perie
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D014344:Trypanocidal Agents