Spotlights on new publications

Abstract

New drug targets-XI Malignant malaria: Active site inhibitors are confronted by high drug pressure, and more susceptibility to parasite gene mutations commonly linked with resistance of anti-malarial drugs. On the other hand, allosteric inhibition (previously described; New drug targets IX, PUJ 2019; 12(1):68-71) is an alternative strategy to design an efficient inhibitor. Briefly, allosteric control means function regulation of a protein by binding an effector molecule at a site other than its active site. Allosteric site allows the effector molecules to activate or inhibit protein functional dynamics. Therefore, allosteric inhibitors are not associated with parasite gene mutation because they don't alter the active site. A group of scientists (Arnold Amusengeri et al.) from South Africa and USA succeeded to identify allosteric modulators (SANC190 and SANC651) against P. falciparum HSP70-1 and HSP70-x. Transcriptomic analysis of P. falciparum revealed six essential HSP70 isoforms; x-z and 1-3. The investigators selected HSP70-1 and HSP70-x because both are maximally expressed during the asexual erythrocytic stages of P. falciparum. Besides, PfHSP70-1 was reported as survival factor, while PfHSP70-x was essential as an efficient exporter of a key virulence factor; erythrocyte membrane protein-1. Studies that utilized atom molecular dynamic simulations to identify allosteric dynamic hotspots for human HSPs 70 and 90 encouraged the investigators to develop promising modulators for PfHSP70-1 and PfHSP70-x.