RESUMO
Plasmepsin 4 (PM4) is a digestive vacuole enzyme found in all Plasmodium species examined to date. While P. falciparum has three additional aspartic proteinases in its digestive vacuole in addition to plasmepsin 4, other Plasmodium species have only PM4 in their digestive vacuole. Therefore, PM4 may be a good target for the development of an antimalarial drug. This study presents data obtained with PM4s from several Plasmodium species. Low nanomolar K(i) values have been observed for all PM4s studied.
Assuntos
Antimaláricos/farmacologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Plasmodium/enzimologia , Inibidores de Proteases/farmacologia , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Animais , Antimaláricos/metabolismo , Ácido Aspártico Endopeptidases/isolamento & purificação , Ácido Aspártico Endopeptidases/metabolismo , Cromatografia de Afinidade , Cromatografia em Gel , Precursores Enzimáticos/metabolismo , Expressão Gênica , Corpos de Inclusão , Modelos Moleculares , Plasmodium/genética , Primaquina/metabolismo , Primaquina/farmacologia , Inibidores de Proteases/metabolismo , Renaturação Proteica , Proteínas de Protozoários/isolamento & purificação , Vacúolos/enzimologiaRESUMO
Clinical treatment-failures to affordable drugs encouraged new investigation for discovery and development of new prophylactic and therapeutic interventions against malaria. The Drug Discovery Cluster (DDcl) of the Italian Malaria Network gathers several highly integrated and complementary laboratories from different Italian Institutions to identify, synthesise, screen in vitro and in vivo new antimalarial molecules directed against the intraerythrocytic stage of P. falciparum parasites and/or with transmission blocking activity to select lead compounds for further development. Complementary research activities, both in vitro and in the clinics, aim at investigating the pathogenetic mechanisms of severe malaria anaemia and the different manifestations of the disease in malaria-HIV co-infected patients to identify new therapies and improve survival.
