Identification of malaria Hsp40 chaperone inhibitors in yeast

描述（由申请人提供）：我们的实验室使用酵母来模拟由涉及神经退行性疾病的人类蛋白质引起的细胞缺陷。此外，我们还研究了真菌病原体对蛋白质折叠机制的依赖性，以发展耐药性。最近，我们开始将这两个研究领域的经验应用于疟疾病原体恶性疟原虫的调查。 恶性疟原虫的基因组非常富含AT，因此编码不寻常量的富含天冬酰胺的蛋白质，预测为非球形的且复杂性低，因此可能对蛋白质折叠机制施加独特的要求。引人注目的是，恶性疟原虫还显示出热休克蛋白40（Hsp40）家族的共伴侣蛋白的显著扩增。恶性疟原虫在其人类宿主的生命周期中感染并重塑红细胞。我们建议，在这个过程中的寄生虫依赖于一个大大扩大类的热休克蛋白40共分子伴侣。 我们已经开发了检测方法来评估Pf Hsp40在酵母中的功能，并试图鉴定抑制这些分子伴侣功能的小分子。特别是，我们专注于Pf Hsp40已被证明是至关重要的寄生虫增殖。将在已建立的寄生虫存活和宿主细胞重塑测定中测试抑制该Hsp40在酵母中的功能的化合物，以阐明该Hsp40在寄生虫生命周期中的作用。 公共卫生相关性：疟疾每年折磨5亿人。引起疟疾的寄生虫在感染过程中似乎依赖于一组称为Hsp40分子伴侣的蛋白质。我们建议确定可以干扰这些蛋白质功能的化合物，希望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.