Small Molecule Inhibitors Against 3C-Like Protease of SARS-CoV-2

项目摘要 人类冠状病毒通常会引起普通感冒，这是一种轻微的上呼吸道疾病，然而，全球 新的人类冠状病毒感染的严重呼吸道疾病的爆发周期性出现， 动物其中包括严重急性呼吸道冠状病毒（SARS-CoV）、中东呼吸综合征（Middle East respiratory syndrome） 冠状病毒（MERS-CoV）和最近的SARS-CoV-2，冠状病毒疾病的病原体2019 （COVID-19）.目前，还没有针对这些病毒的许可疫苗或抗病毒药物， 迫切需要制定针对冠状病毒的预防和治疗措施。状病毒 基因组编码大的多聚蛋白，其由3C样蛋白酶（3CLpro）和木瓜蛋白酶样蛋白酶（3CLpro）加工。 蛋白酶这两种蛋白酶都是病毒复制所必需的，使它们成为药物开发的有吸引力的靶点。 我们在这一领域的尝试已经导致了多种病毒的广谱抑制剂的发现，包括 编码3CLpro的冠状病毒和诺如病毒，以及首次通过 猫冠状病毒3CLpro抑制剂。最近，我们已经证明了二肽基系列化合物 在细胞培养中有效抑制人冠状病毒，包括MERS-CoV和SARS-CoV-2，并在体内展示 在MERS-CoV感染的DPP 4-KI小鼠模型中的有效性。化合物的抗病毒靶点为 通过获得来自SARS-CoV、SARS-CoV和SARS-CoV的高分辨率晶体结构3CL前抑制剂复合物来验证。 CoV-2和MERS CoV。我们在此假设，所识别的系列可以作为 开发SARS-CoV-2特异性抗病毒药物。拟议研究的直接和首要目标是 进一步优化已鉴定的SARS-CoV-2先导抑制剂的药理活性PK参数 3CLpro和针对SARS-CoV-2的体内功效的证明。我们研究的预期结果是 选择非常适合进行进一步研究的临床前候选物（和1-2种备用化合物） 临床前研究，最终导致COVID-19特异性抗病毒治疗的开发。

PROJECT SUMMARY Human coronaviruses generally cause the common cold, a mild upper respiratory illness, however, global outbreaks of new human coronavirus infections with severe respiratory disease have periodically emerged from animals. These include Severe Acute Respiratory coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and, most recently, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). Currently, there are no licensed vaccines or antiviral drugs against these viruses, underscoring an urgent need for the development of preventive and therapeutic measures against coronaviruses. Coronavirus genomes encode large polyproteins which are processed by a 3C-like protease (3CLpro) and a papain-like protease. Both proteases are essential for viral replication, making them attractive targets for drug development. Our foray in this area has resulted in the discovery of broad-spectrum inhibitors of multiple viruses, including coronaviruses and noroviruses that encode 3CLpro, as well as the first demonstration of clinical efficacy by a feline coronavirus 3CLpro inhibitor. Recently, we have demonstrated that a dipeptidyl series of compounds potently inhibit human coronaviruses, including MERS-CoV and SARS-CoV-2 in cell culture, and display in vivo efficacy in the DPP4-KI mouse model of MERS-CoV infection. The antiviral target of the compounds was validated by obtaining high resolution crystal structures 3CLpro-inhibitor complexes from SARS-CoV, SARS- CoV-2 and MERS-CoV. We hypothesize herein that the identified series can serve as a launching pad for the development of SARS-CoV-2-specific antivirals. The immediate and overarching goal of the proposed studies is to further optimize the pharmacological activity PK parameters of identified lead inhibitors of SARS-CoV-2 3CLpro and the demonstration of in vivo efficacy against SARS-CoV-2. The expected outcome of our studies is the selection of a preclinical candidate (and 1-2 backup compounds) that is well-suited to conducting further preclinical studies, ultimately leading to the development of a COVID-19-specific antiviral therapeutic.