title: Design and synthesis of protein-protein interaction mimics as Plasmodium falciparum cysteine protease, falcipain-2 inhibitors.
abstract: Small peptides that mimic the protein-protein interactions between falcipain-2 and egg white cystatin, an endogenous inhibitor of cysteine proteases, were designed and synthesized and their effects on falcipain-2 activity were analyzed. The mimics are characterized by the presence of different linkers: γ-aminobutyric acid, cis-4-aminocyclohexane carboxylic acid and a macrocycle formed by GABA and two cysteines joined by a disulfide linkage. Some of these compounds showed falcipain-2 inhibition in the micromolar range and produced morphological abnormalities in the Plasmodium food vacuole. Although these peptides are less potent than cystatin, considering the reduction of amino acid residues and the capacity to cross membranes, this approach could be an interesting starting point for the development of a new class of anti-malarial drugs.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Facoltà di Farmacia, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rizzi
authors.forename: Srividhya
authors.initials: S
authors.lastname: Sundararaman
authors.forename: Katarina
authors.initials: K
authors.lastname: Cendic
authors.forename: Nadia
authors.initials: N
authors.lastname: Vaiana
authors.forename: Reshma
authors.initials: R
authors.lastname: Korde
authors.forename: Dipto
authors.initials: D
authors.lastname: Sinha
authors.forename: Asif
authors.initials: A
authors.lastname: Mohmmed
authors.forename: Pawan
authors.initials: P
authors.lastname: Malhotra
authors.forename: Sergio
authors.initials: S
authors.lastname: Romeo
mesh_terms: D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D003546:Cysteine Endopeptidases; C416224:falcipain 2