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: gamma-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.

Design and synthesis of protein–protein interaction mimics as plasmodium falciparum cysteine protease, falcipain-2 inhibitors / L. Rizzi, S. Sundararaman, K. Cendic, N. Vaiana, R. Korde, D. Sinha, A. Mohmmed, P. Malhotra, S. Romeo. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 46:6(2011 Jun), pp. 2083-2090. [10.1016/j.ejmech.2011.02.061]

Design and synthesis of protein–protein interaction mimics as plasmodium falciparum cysteine protease, falcipain-2 inhibitors

L. Rizzi
Primo
;
K. Cendic;N. Vaiana;S. Romeo
Ultimo
2011-06

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: gamma-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.
Cystatin; Falcipain-2; Malaria; Protein-protein interaction mimics
Settore CHIM/08 - Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/156635
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