Plasmodial heat shock proteins: targets for chemotherapy.
Heat shock proteins act as molecular chaperones, facilitating protein folding in cells of living organisms. Their role is particularly important in parasites because environmental changes associated with their life cycles place a strain on protein homoeostasis. Not surprisingly, some heat shock proteins are essential for the survival of the most virulent malaria parasite, Plasmodium falciparum. This justifies the need for a greater understanding of the specific roles and regulation of malarial heat shock proteins. Furthermore, heat shock proteins play a major role during invasion of the host by the parasite and mediate in malaria pathogenesis. The identification and development of inhibitor compounds of heat shock proteins has recently attracted attention. This is important, given the fact that traditional antimalarial drugs are increasingly failing, as a consequence of parasite increasing drug resistance. Heat shock protein 90 (Hsp90), Hsp70/Hsp40 partnerships and small heat shock proteins are major malaria drug targets. This review examines the structural and functional features of these proteins that render them ideal drug targets and the challenges of targeting these proteins towards malaria drug design. The major antimalarial compounds that have been used to inhibit heat shock proteins include the antibiotic, geldanamycin, deoxyspergualin and pyrimidinones. The proposed mechanisms of action of these molecules and the pathways they inhibit are discussed.
Shonhai
Addmore
A
Department of Biochemistry & Microbiology, Zululand University, Kwadlangezwa, South Africa. adshon@gmail.com
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010961:Plasmodium / Q000187:drug effects* / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000962:Antimalarials; D016227:Benzoquinones; D006146:Guanidines; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011744:Pyrimidinones; C037258:gusperimus; C001277:geldanamycin