Development of peptidomimetics with a vinyl sulfone warhead as irreversible falcipain-2 inhibitors.
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.
Ettari
Roberta
R
Dipartimento Farmaco-Chimico, University of Messina, Viale Annunziata, 98168 Messina, Italy. rettari@pharma.unime.it
Nizi
Emanuela
E
Di Francesco
Maria Emilia
ME
Dude
Marie-Adrienne
MA
Pradel
Gabriele
G
Vicík
Radim
R
Schirmeister
Tanja
T
Micale
Nicola
N
Grasso
Silvana
S
Zappalà
Maria
M
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
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