6533b826fe1ef96bd1284782

RESEARCH PRODUCT

Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment.

Roberta EttariGiorgio AmendolaUte A. HellmichAnnika WagnerSanto PrevitiMaria ZappalàSantina MaioranaSandro CosconatiTanja Schirmeister

subject

KetoneStereochemistryTrypanosoma brucei bruceiTrypanosoma bruceiCysteine Proteinase Inhibitors01 natural sciencesBiochemistrycathepsin LCathepsin LStructure-Activity RelationshipParasitic Sensitivity TestsDrug DiscoveryTrypanosoma bruceiGeneral Pharmacology Toxicology and PharmaceuticsPharmacologychemistry.chemical_classificationrhodesainbiologyDose-Response Relationship DrugMolecular Structure010405 organic chemistryOrganic ChemistryselectivityTrypanosoma brucei rhodesienseKetonesbiology.organism_classificationCysteine proteaseTrypanocidal Agents0104 chemical sciences010404 medicinal & biomolecular chemistryCysteine EndopeptidasesEnzymechemistrybiology.proteinMolecular MedicineMichael acceptorSelectivityPeptides

description

In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure-activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range.

yearjournalcountryeditionlanguage
2020-07-07ChemMedChem
10.1002/cmdc.202000360https://pubmed.ncbi.nlm.nih.gov/32567172