Malaria is currently endemic in 106 countries, with an estimated 216 million clinical cases and nearly 655000 deaths in 2010 [1]. Five species of a parasite of Plasmodium genus are infective for humans, with the most severe form of malaria caused by P. falciparum species.The increasing resistance of malaria parasites to antimalarial drugs, the lack of widely available vaccines that provide a high level of protection for a sustained period, and the inadequate control of mosquito vectors demand new approaches to drug development. One promising strategy to develop new drugs has been to target proteases of malaria parasites which play pivotal roles in the processes of host erythrocyte rupture, erythrocyte invasion, and hemoglobin degradation. Falcipain-2 (FP-2) of P. falciparum is a papain-family (clan CA, family C1) cysteine protease and is likely the major hemoglobinase in the food vacuole of erythrocytic parasites. FP-2 is also able to promote host cell rupture cleaving erythrocyte membrane skeletal proteins. Therefore, the inhibition of FP-2 represents a promising strategy for discovery of novel anti-malarial drugs. Our research group has actively been involved on the synthesis of novel peptidomimetic FP-2 inhibitors containing a 1,4-benzodiazepine scaffold [2-6], introduced internally to a peptide sequence which mimics the dipeptide D-Ser-Gly, and different electrophilic warheads able to interact with the thiol group of the cysteine active site by forming a reversible or irreversible covalent bond. Several of the newly synthesized peptidomimetics turned out to be potent and selective FP-2 inhibitors and showed a good selectivity towards human cathepsin B and L. The obtained results have been rationalized on the basis of docking experiments. These studies helped us to identify the structural requirements that are essential for the interaction with the target and in determining the binding mode of these type of inhibitors.
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF PEPTIDOMIMETIC FALCIPAIN-2 INHIBITORS AS ANTIMALARIAL AGENTS / N. Micale, R. Ettari, T. Schirmeister, G. Grazioso, S. Grasso, M. Zappalà. ((Intervento presentato al 6. convegno Nuove prospettive in chimica farmaceutica tenutosi a Riccione nel 2012.
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF PEPTIDOMIMETIC FALCIPAIN-2 INHIBITORS AS ANTIMALARIAL AGENTS
G. Grazioso;
2012
Abstract
Malaria is currently endemic in 106 countries, with an estimated 216 million clinical cases and nearly 655000 deaths in 2010 [1]. Five species of a parasite of Plasmodium genus are infective for humans, with the most severe form of malaria caused by P. falciparum species.The increasing resistance of malaria parasites to antimalarial drugs, the lack of widely available vaccines that provide a high level of protection for a sustained period, and the inadequate control of mosquito vectors demand new approaches to drug development. One promising strategy to develop new drugs has been to target proteases of malaria parasites which play pivotal roles in the processes of host erythrocyte rupture, erythrocyte invasion, and hemoglobin degradation. Falcipain-2 (FP-2) of P. falciparum is a papain-family (clan CA, family C1) cysteine protease and is likely the major hemoglobinase in the food vacuole of erythrocytic parasites. FP-2 is also able to promote host cell rupture cleaving erythrocyte membrane skeletal proteins. Therefore, the inhibition of FP-2 represents a promising strategy for discovery of novel anti-malarial drugs. Our research group has actively been involved on the synthesis of novel peptidomimetic FP-2 inhibitors containing a 1,4-benzodiazepine scaffold [2-6], introduced internally to a peptide sequence which mimics the dipeptide D-Ser-Gly, and different electrophilic warheads able to interact with the thiol group of the cysteine active site by forming a reversible or irreversible covalent bond. Several of the newly synthesized peptidomimetics turned out to be potent and selective FP-2 inhibitors and showed a good selectivity towards human cathepsin B and L. The obtained results have been rationalized on the basis of docking experiments. These studies helped us to identify the structural requirements that are essential for the interaction with the target and in determining the binding mode of these type of inhibitors.
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