ABSTRACT
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.
Subject(s)
Antimalarials/pharmacology , Insecticides/pharmacology , Societies, Scientific/organization & administration , Animals , Anopheles/drug effects , Anopheles/metabolism , Anopheles/parasitology , Antimalarials/therapeutic use , Biological Products/pharmacology , Biological Products/therapeutic use , Drug Delivery Systems , Drug Design , Drug Evaluation, Preclinical , Drug Resistance , Humans , Insect Vectors/drug effects , Insect Vectors/metabolism , Insect Vectors/parasitology , Insecticides/therapeutic use , Italy , Kynurenine/metabolism , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Malaria, Falciparum/transmission , Mice , Mice, Inbred BALB C , Parasitic Sensitivity Tests , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plasmodium falciparum/drug effectsABSTRACT
Catechins are able to modulate the gelatinolytic activity of matrix metalloproteinase-9 (MMP-9) by reducing its release from macrophages. Gallocatechins decrease MMP-9 secretion by lowering MMP-9 promoter activity and mRNA levels. The effect appears to be dependent on some structural and stereochemical requirements. In this study, the relationship between chemical structure and activity was studied by testing the effect of analogues of (+/-)-gallocatechin-3-gallate (+/-)-GCG, selectively deprived of hydroxyl groups, on MMP-9 activity, transcription, and secretion. Our results indicate that (+/-)-GCG and (+/-)-catechin-3-gallate are characterized by a substitution pattern compatible with direct inhibition of MMP-9 activity. Conversely, when transcription was the target, (+/-)-trans-3-flavanol-3-benzoate, lacking all the hydroxyl groups, was the most effective both in lowering MMP-9 promoter activity and consequently protein secretion, and in inhibiting nuclear-factor-kappaB-driven transcription. Our results suggest that the structural requirements for enzyme inhibition are different from those necessary for targeting gene expression.