RESUMO
The etiological agent of the most dangerous form of malaria, Plasmodium falciparum, has developed resistance or reduced sensitivity to the majority of the drugs available to treat this deadly disease. Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease subtilisin-like protease 1 (PfSUB1) has been identified as a key enzyme for merozoite egress from red blood cells and invasion. We present herein the rational design, synthesis, and biological evaluation of novel and potent difluorostatone-based inhibitors. Our bioinformatic-driven studies resulted in the identification of compounds 1a, b as potent and selective PfSUB1 inhibitors. The enzyme/inhibitor interaction pattern herein proposed will pave the way to the future optimization of this class of promising enzyme inhibitors.
Assuntos
Desenho de Fármacos , Oligopeptídeos/farmacologia , Plasmodium falciparum/enzimologia , Inibidores de Proteases/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Subtilisinas/antagonistas & inibidores , Relação Dose-Resposta a Droga , Modelos Moleculares , Conformação Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Subtilisinas/metabolismoRESUMO
Peptidic α-ketoamides have been developed as inhibitors of the malarial protease PfSUB1. The design of inhibitors was based on the best known endogenous PfSUB1 substrate sequence, leading to compounds with low micromolar to submicromolar inhibitory activity. SAR studies were performed indicating the requirement of an aspartate mimicking the P1' substituent and optimal P1-P4 length of the non-prime part. The importance of each of the P1-P4 amino acid side chains was investigated, revealing crucial interactions and size limitations.