Aspartic Protease Inhibitors as Novel Antimalarials

描述(申请人提供)：疟疾是一种破坏性疾病，每年影响超过10亿人，造成约100万人死亡。尽管有许多药物用于治疗这种疾病，但对这些药物的抗药性正在变得越来越普遍。对抗抗药性寄生虫的优秀长期解决方案需要确定新的抗疟疾药物靶标和通过独特的作用机制杀死寄生虫的化合物类别。恶性疟原虫是对人类最致命的物种，以及其他导致疟疾的疟原虫物种，它们有多种天冬氨酸蛋白酶，对寄生虫的生存至关重要。我们建议(1)优化两类天冬氨酸蛋白酶抑制剂的抗疟疾活性，(2)确定它们作为抗疟疾药物的独特作用机制。通过我们的初步合作，我们已经确定了具有内在抗疟疾活性和口服疗效的类药物天冬氨酸蛋白酶抑制剂，以进行适当的优化，作为药物。为了有效地满足对新型抗疟疾药物的迫切需求，圣路易斯大学世界卫生与医学中心(CWHM)与中国科学院广州生物医学与健康研究所(GIBH)建立了研究合作关系。CWHM是一家非营利性机构，由高技能和成功的前辉瑞药物发现科学家组成，他们擅长将基础科学转化为 发现和开发具有挑战性的靶点的新药。GIBH是中国领先的疟疾生物学、药物研发和药物化学专业中心。这一独特的合作包括成功证明新型天冬氨酸蛋白酶抑制剂作为抗疟疾药物的可行性以及确定其作用机制(S)以用于靶向药物发现所需的专业知识和资源。

DESCRIPTION (provided by applicant): Malaria is a devastating disease that affects over one billion people and causes approximately 1 million deaths annually. Although there are a number of drugs used to treat the disease, resistance to these drugs is becoming more widespread. Superior long-term solutions for combatting resistant parasites require identification of novel antimalarial drug targets and compound classes that kill the parasite with unique mechanisms of action. Plasmodium falciparum, the most deadly species to humans, as well as other malaria- causing species of Plasmodium, have multiple aspartic proteases that are essential to the parasite's survival. We propose to (1) optimize the antimalarial activity of two classes of asparti protease inhibitors and (2) determine their unique mechanism of action as antimalarial agents. Through our preliminary collaborative efforts, we have already identified drug-like aspartic protease inhibitors with inherent antimalarial activity and oral efficacy for suitable optimizationas drugs. In order to efficiently address the critical need for novel antimalarials, the Center for World Health & Medicine (CWHM) at Saint Louis University has established a research collaboration with the Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences. CWHM is a non-profit institute comprised of highly skilled and successful former Pfizer drug discovery scientists with expertise in the translation of basic science into the discovery and development of novel drugs for challenging targets. GIBH is a leading Chinese center of expertise in malaria biology, drug discovery and medicinal chemistry. This unique collaboration encompasses the expertise and resources necessary to successfully demonstrate the viability of novel aspartic protease inhibitors as antimalarial agents and to determine of thei mechanism(s) of action for target-based drug discovery.