Heat Shock Proteins as Targets for Novel Anti-Malarial Drugs
Molecular chaperones or heat shock proteins are involved in diverse biological processes and play an important role in maintaining cellular homeostasis. Thus, inhibiting their function can be detrimental to cell survival. It has been well established that elaborate involvement of heat shock proteins is required during the process of malaria pathogenesis. Hence, heat shock proteins serve as potential drug targets against malaria. The emergence of drug resistance in Plasmodium falciparum against existing anti-malarial drugs has created a pressing need for the identification of novel drug targets. Multiple strategies have been undertaken in this regard which involve target based drug discovery, identifying novel anti-malarial natural compounds, chemically modifying existing drugs or repurposing drugs used for other diseases. This chapter provides a comprehensive overview of the inhibitors of Hsp90 and Hsp70-40 molecular chaperone system tested for efficacy in Plasmodium falciparum. These compounds belong to diverse chemical families and are of both natural and synthetic origin. Naturally occurring napthoquinones and synthetic pyrimidinones target PfHsp70 function while geldanamycin, acrisorcin, APPA and harmine are natural compounds that inhibit PfHsp90 function. Some of these compounds like geldanamycin and its derivative 17-AAG have been also tested in the mouse model of malaria and have been found to be very effective. Overall, heat shock protein inhibitors not only provide us with a new avenue to tackle malaria but also shed light on novel features of parasite’s biology.
KeywordsHsp90 Hsp70 Anti-malarial Geldanamycin Pyrimidinone Napthoquinone
- Acharya P, Kumar R, Tatu U (2007) chaperoning a cellular upheaver in malaria: heat shock proteins in Plasmodium faliciprum. Mol Biochem Parasitol 153: 85-94Google Scholar
- DeBoer C, Dietz A (1976) The description and antibiotic production of Streptomyces hygroscopicus var. Geldanus. J Antibiot (Tokyo) 29:1182–1188Google Scholar
- Kitson RRA, Moody CJ (2013) Learning from Nature: Advances in Geldanamycin- and Radicicol-based inhibitors of Hsp90. J Org Chem 78:5117–5141 . doi: 10.1021/jo4002849Google Scholar
- Pallavi R, Roy N, Nageshan RK, Talukdar P, Pavithra SR et al (2010) Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug. J Biol Chem 285:37964–37975PubMedCrossRefGoogle Scholar
- Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 91:8324–8328PubMedCrossRefGoogle Scholar