Our laboratory has used yeast to model the cellular defects caused by the human proteins implicated in neurodegenerative diseases. Furthermore, we have studied the reliance of fungal pathogens on the protein folding machinery to evolve drug resistance. Recently, we have begun to apply the lessons we learned from these two research areas to the investigation of the malaria pathogen Plasmodium falciparum. The genome of P. falciparum is very AT-rich and consequently encodes an unusual amount of asparagine-rich proteins, predicted to be non-globular and of low complexity and thus likely to impose unique demands on the protein folding machinery. Strikingly, P. falciparum also shows a marked expansion of the heat shock protein 40 (Hsp40) family of co-chaperones. During its life cycle in its human host P. falciparum infects and remodels red blood cells. We propose that during this process the parasite relies on a greatly expanded class of Hsp40 co-chaperones. We have developed assays to assess the function of Pf Hsp40s in yeast and we seek to identify small molecules that inhibit the functions of those chaperones. In particular we focus on a Pf Hsp40 that has been shown to be crucial to parasite proliferation. Compounds inhibiting the function of this Hsp40 in yeast will be tested in established parasite survival and host cell remodeling assays to elucidate the role of this Hsp40 in the parasite life cycle.
Malaria afflicts 500 million people a year. The parasite causing malaria appears to rely on a set of proteins called Hsp40 chaperones during its infection. We propose to identify compounds that can interfere with the function of these proteins in the hope of ultimately developing a new class of anti-malarial drugs.