The possibilities and challenges associated with selective targeting Plasmodium falciparum Hsp90 for Malaria

The causative agent of malaria, Plasmodium falciparum, encodes four heat shock protein 90 isoforms in the cytosol, endoplasmic reticulum, mitochondria and apicoplast. PfHsp90s are considered potential targets for developing antimalarial drugs. However, the similarity between the druggable ATP binding pocket of these isoforms and their human counterparts has hindered efforts in discovering Hsp90-based antimalarial drugs. There is widespread concern that the chemotypes targeting PfHsp90 isoforms may not possess the selectivity required for translatability. Most studies have focused on the cytosolic (canonical Hsp90) and have used various inhibitors of Hsp90 to conduct anti-Plasmodium and mammalian safety studies without considering the on-target enzymatic activity and binding affinity. The extent to which the cytosolic Hsp90 shares common mechanisms with the other isoforms remains elusive. As such, detailed structural comparisons of the Hsp90 isoforms may reveal exploitable differences that could favour preferential binding. It is essential to consider whether molecules that act as pan-inhibitors would put more pressure on the parasite or have detrimental effects. Studies should go beyond molecular docking and whole-cell activity to advance the development of Hsp90 inhibitors as future antimalarials. There is a need also to assess the physicochemical properties, drug metabolism, pharmacokinetics, and In vivo proof-of-concept. We argue that the potential benefits of PfHsp90 isoform inhibitors outweigh the off-target and selectivity risks. Additionally, opportunities for using machine learning and computer-aided drug discovery efforts to design inhibitors that preferentially bind to each isoform, particularly the cytosolic PfHsp90, are highlighted as a means of overcoming the resistance challenge.