Identification of malaria Hsp40 chaperone inhibitors in yeast

描述(由申请人提供)：我们的实验室已经使用酵母来模拟与神经退行性疾病有关的人类蛋白引起的细胞缺陷。此外，我们还研究了真菌病原体对蛋白质折叠机制的依赖，以进化耐药。最近，我们开始将这两个研究领域的经验教训应用到疟疾病原体恶性疟原虫的调查中。恶性疟原虫基因组富含AT，因此编码了大量富含天冬酰胺的蛋白质，预计这些蛋白质是非球形的，复杂性较低，因此可能对蛋白质折叠机制提出独特的要求。值得注意的是，恶性疟原虫还显示出热休克蛋白40(Hsp40)辅助伴侣家族的显著扩大。在其人类宿主的生命周期中，恶性疟原虫感染并重塑红细胞。我们认为，在这个过程中，寄生虫依赖于大大扩展的Hsp40辅助伴侣。我们已经开发了评估酵母中Pf Hsp40s功能的方法，并试图确定抑制这些伴侣功能的小分子。特别是，我们将重点放在已被证明对寄生虫增殖至关重要的Pf Hsp40。抑制该HSP40在酵母中的功能的化合物将在已建立的寄生虫存活和宿主细胞重塑试验中进行测试，以阐明该HSP40在寄生虫生命周期中的作用。 与公共卫生相关：每年有5亿人罹患疟疾。这种导致疟疾的寄生虫似乎在感染过程中依赖于一组名为Hsp40伴侣的蛋白质。我们建议鉴定能够干扰这些蛋白质功能的化合物，以期最终开发出一类新的抗疟疾药物。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.