Biochemistry of Protein Prenylation

描述（由申请人提供）：蛋白质法尼基化是在真核细胞中将15碳法尼基连接到蛋白质的c端。我们已经证明，这种翻译后修饰发生在锥虫和疟疾中，它们是导致毁灭性热带疾病的寄生虫。我们还发现，将法尼基基团附着在寄生虫蛋白上的酶——蛋白法尼基转移酶（protein farnesyltransferase， PFT）是开发新型药物的一个很好的靶标，这种药物可以不可逆地抑制引起非洲昏睡病（布氏锥虫）和疟疾（恶性疟原虫）的寄生虫的生长。我们在设计和发现寄生虫PFTs的有效抑制剂方面取得了相当大的进展，这些抑制剂可以阻断培养物中寄生虫的生长，也可以治愈被寄生虫感染的实验性啮齿动物。然而，我们最好的化合物还不足以进入临床试验，因为它们的代谢速度太快，不能在3天的时间内每天给药一次或两次，而这是治疗热带疾病的最佳剂量计划。我们希望继续应用结构导向药物化学的原理来改善我们的PFT抑制剂的药物样性质。体外评估药物代谢和肠道吸收将用于筛选有效的PFT抑制剂。我们的最佳化合物将进一步探索对寄生虫感染的啮齿动物的功效。我们的总体目标是开发治疗寄生虫病的新药，寄生虫病给全世界数百万人带来痛苦。公共卫生相关性：我们工作的相关性是发现治疗破坏性热带疾病疟疾和非洲昏睡病的新疗法。疟疾和非洲昏睡病每年分别导致约200万人和20万人死亡。因为现有的药物要么无效，要么产生了耐药性，所以需要新的药物。

DESCRIPTION (provided by applicant): Protein farnesylation is the attachment of the 15-carbon farnesyl group to the C-termini of proteins in eukaryotic cells. We have shown that this post-translational modification occurs in trypanosomatids and malaria, parasites that cause devastating tropical diseases. We have also shown that the enzyme that attaches farnesyl groups to parasite proteins, protein farnesyltransferase (PFT), is a good target for the development of novel drugs that irreversibly inhibit the growth of the parasite that causes African sleeping sickness (Trypanosoma brucei) and malaria (Plasmodium falciparum). We have made considerable progress in the design and discovery of potent inhibitors of parasite PFTs that block the growth of parasites in culture and also cure experimental rodents infected with parasites. However, our best compounds are not good enough to advance into clinical trials because they are metabolized too quickly to allow for once or twice daily dosing over a 3-day period, a dose schedule that is optimal for treatment of tropical diseases. We want to continue to apply the principles of structure-guided medicinal chemistry to improve the drug-like properties of our PFT inhibitors. In vitro assessment of drug metabolism and intestinal absorption will be used to screen potent PFT inhibitors. Our best compounds will be further explored for efficacy in parasite- infected rodents. Our overall goal is to develop new drugs for the treatment of parasitic diseases that cause suffering among millions of people worldwide. PUBLIC HEALTH RELEVANCE: The relevance of our work is to discover new therapeutics for the treatment of the devastating tropical diseases malaria and African sleeping sickness. Malaria and African sleeping sickness kill about 2 million and 200,000 people, respectively, each year. New drugs are needed because existing drugs are either ineffective or resistance has developed.