CATHEPSIN L INHIBITORS AS PAN-CORONAVIRUS THERAPEUTICS

 描述（由申请方提供）：冠状病毒（CoV）是一种RNA病毒，可在几种哺乳动物中引起胃肠道、呼吸道和神经系统症状。2002年爆发的严重急性呼吸道综合征冠状病毒（SARS-CoV）在人类中的感染患者中约有10%是致命的，感染了约8000人，造成800人死亡。最近涉及高致病性中东呼吸综合征CoV（MERS CoV）的事件表明，致病性CoV从动物到人类的出现可能随时发生。目前还没有FDA批准的药物可用于治疗SARS或MERS;因此，开发治疗CoV感染的治疗剂是一个基本的、未满足的医疗需求。由于进入宿主细胞是病毒生命周期的第一步，因此该aea为治疗和预防提供了主要靶点。CoV编码三种表面蛋白，并且刺突S蛋白必须被人组织蛋白酶L（CatL）蛋白水解才能正确进入。几种冠状病毒利用这种关键的人类蛋白酶CatL进入的事实为开发泛冠状病毒抑制剂药物提供了机会。我们的目标是通过探索导致在活细胞测定中抑制SARS-CoV和MERS-CoV感染的主侧α-螺旋结合口袋来产生CatL的有效的、特异性的先导抑制剂，并在CoV感染的动物模型中进行测试的途中分析ADME/毒理学性质。

 DESCRIPTION (provided by applicant): Coronaviruses (CoV) are RNA viruses that cause gastrointestinal, respiratory, and neurological symptoms in several mammalian species. The outbreak of the severe acute respiratory syndrome CoV (SARS-CoV) in humans 2002 was fatal in ~10% of infected patients, infecting ~8000 people and killing 800. The recent incidents involving the highly pathogenic Middle East Respiratory Syndrome CoV (MERS-CoV) demonstrate that the emergence of pathogenic CoVs from animals to humans can occur at any time. There are currently no FDA approved drugs available for treatment of either SARS or MERS; thus, the development of therapeutic agents to treat CoV infections is an essential, unmet medical need. Because entry into host cells is the first step in the viral life cycle, this aea offers a major target for treatment and prevention. CoVs encode three surface proteins, and the spike S protein must be proteolyzed by human cathepsin L (CatL) for proper entry. The fact that several CoVs utilize this key human protease, CatL, for entry offers an opportunity to develop pan-anticoronavirus inhibitor drugs. We aim to generate potent, specific lead inhibitors for CatL via exploration of the prime side a-helical binding pocket that results in inhibition of SARS-CoV and MERS-CoV infection in live cell assays, and to analyze ADME/toxicology properties en route to testing in animal models of CoV infection.