Structure-based drug discovery of species- selective inhibitors of Hsp90

Abstract

The protozoan parasite Plasmodium falciparum (Pf) has to cope with perpetual environmental stresses during its whole lifecycle. As an adaptation to this, the parasite resorts to a sophisticated system of molecular chaperones. Hsp90 is one of the most important molecular chaperones that help regulate numbers of biological processes such as signal transduction, cell cycle control, hormone signaling, transcription, heat shock response, etc. Additional evidence suggested that Hsp90 is involved in the development of the parasite and its pathogenesis during the infection. The Hsp90 inhibitor geldanamycin has been found to be effective against infection by Plasmodium yoelli in a mouse model. These results suggested that Hsp90 inhibitors may have great potential as new antimalarial agents. As most of the known antimalarials intervene during the blood-stages of the infection, the design of antimalarial drugs should maximally evade human off targets on which impact may potentially elicit toxicity. But many drug targets are actually essential proteins that are functionally and structurally conserved. This fact hinders the therapeutic exploitation of many promising drug targets. Hsp90 might be among them. Hsp90s are highly conserved between Pf and human. There are only three substitutions found in the drug-binding pocket, which account for a 92% of conservation in protein sequences. Such high degree of homology hinders the discovery of species-specific inhibitors. Is there still a chance for Hsp90 to become an antimalarial target? The work presented in this thesis is a “hunt” for selective inhibitors against PfHsp90 using structure-based drug design (SBDD). We have elaborated a strategy of SBDD based on comparative analyses of the drug-binding pocket between PfHsp90 and its human counterparts. Furthermore, we have established several in vivo and in vitro systems as tools for step-wise drug validation. The combination of the efforts allowed us to discover a lead molecule, IND31119, that inhibits exclusively PfHsp90 while bypassing its highly similar human orthologs. Our work illustrates a new trend in drug discovery that involves a highly dynamic cooperation across biology, chemistry and computer science. Our publication also represented the first report that confirmed the feasibility of designing selective inhibitors against PfHsp90. My thesis can pave the way for translational research into PfHsp90 inhibitors as new weapons in the fight against malaria.