title: Development of peptidomimetics with a vinyl sulfone warhead as irreversible falcipain-2 inhibitors.
abstract: This paper describes the synthesis of a new class of peptidomimetic cysteine protease inhibitors based on a 1,4-benzodiazepine scaffold and on an electrophilic vinyl sulfone moiety. The former was introduced internally to a peptide sequence that mimics the fragment D-Ser-Gly; the latter was built on the P1-P1' site and reacts as a classical "Michael acceptor", leading to an alkylated enzyme by irreversible addition of the thiol group of the active site cysteine. The introduction of the vinyl sulfone moiety has been accomplished by olefin cross-metathesis, a powerful tool for the formation of carbon-carbon double bonds. New compounds 2-3 have been proven to be potent and selective inhibitors of falcipain-2, a cysteine protease isolated from Plasmodium falciparum, displaying antiplasmodial activity.
authors.affiliation: Dipartimento Farmaco-Chimico, University of Messina, Viale Annunziata, 98168 Messina, Italy. rettari@pharma.unime.it
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.forename: Maria Emilia
authors.initials: ME
authors.lastname: Di Francesco
authors.forename: Marie-Adrienne
authors.initials: MA
authors.lastname: Dude
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.forename: Radim
authors.initials: R
authors.lastname: Vicík
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000737:chemistry; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D002219:Carbamates; D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D011994:Recombinant Proteins; D013450:Sulfones; D001569:Benzodiazepines; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L