Peptidomimetics containing a vinyl ketone warhead as falcipain-2 inhibitors

Roberta Ettari; Maria Zappalà; Nicola Micale; Giovanni Grazioso; Salvatore Giofrè; Tanja Schirmeister; Silvana Grasso

doi:10.1016/j.ejmech.2011.02.058

Peptidomimetics containing a vinyl ketone warhead as falcipain-2 inhibitors

Eur J Med Chem. 2011 Jun;46(6):2058-65. doi: 10.1016/j.ejmech.2011.02.058. Epub 2011 Mar 3.

Authors

Roberta Ettari¹, Maria Zappalà, Nicola Micale, Giovanni Grazioso, Salvatore Giofrè, Tanja Schirmeister, Silvana Grasso

Affiliation

¹ Dipartimento Farmaco-Chimico, University of Messina, Viale Annunziata, 98168 Messina, Italy. rettari@pharma.unime.it

PMID: 21420760
DOI: 10.1016/j.ejmech.2011.02.058

Abstract

The design, chemical synthesis, and enzymatic activity evaluation of a set of falcipain-2 inhibitors are reported. These compounds contain a proven peptidomimetic recognition motif based on a benzo[1,4]diazepin-2-one (1,4-BDZ) framework built on a dipeptide sequence, and a Michael acceptor terminal moiety capable of deactivating the cysteine protease active site. Our goal is to modify the P(3) site of this motif in order to identify the structural requirements for the interaction with the target.

Publication types

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

MeSH terms

Benzodiazepinones / chemical synthesis
Benzodiazepinones / chemistry
Benzodiazepinones / pharmacology*
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
Drug Design
Enzyme Activation / drug effects
Humans
Models, Molecular
Molecular Structure
Peptidomimetics*
Stereoisomerism
Structure-Activity Relationship

Substances

Benzodiazepinones
Cysteine Proteinase Inhibitors
Peptidomimetics
benzo(1,4)diazepin-2-one
Cysteine Endopeptidases
falcipain 2