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

项目总结 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， 新的人类冠状病毒感染与严重呼吸道疾病的暴发周期性地出现在 动物。这些病毒包括严重急性呼吸道冠状病毒(SARS-CoV)、中东呼吸综合征 冠状病毒(MERS-CoV)，以及最近的SARS-CoV-2,2019年冠状病毒病的病原体 (新冠肺炎)。目前，没有获得许可的疫苗或抗病毒药物来对抗这些病毒，这突显了 迫切需要制定预防和治疗冠状病毒的措施。冠状病毒 基因组编码大的多聚蛋白，这些蛋白由一个类似3C的蛋白酶(3CLpro)和一个类似木瓜的酶处理 蛋白酶。这两种酶对病毒复制都是必不可少的，使它们成为药物开发的有吸引力的目标。 我们在这一领域的尝试已经发现了多种病毒的广谱抑制剂，包括 编码3CLPro的冠状病毒和诺如病毒，以及通过一种 猫冠状病毒3CLPro抑制剂。最近，我们已经证明了一种二肽基系列化合物 在细胞培养中有效抑制包括MERS-CoV和SARS-CoV-2在内的人类冠状病毒，并在体内展示 DPP4-KI小鼠MERS冠状病毒感染模型的疗效。这些化合物的抗病毒靶点是 从SARS-CoV、SARS-CoV和SARS-CoV获得高分辨晶体结构3CLPro-抑制剂复合体的验证 CoV-2和MERS-CoV。我们在此假设，已识别的系列可以作为 SARS-CoV-2特异性抗病毒药物的研究进展拟议研究的直接和总体目标是 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和体内抗SARS-CoV-2效果的演示。我们研究的预期结果是 选择一种临床前候选化合物(和1-2种备用化合物)，该化合物非常适合进行进一步研究 临床前研究，最终导致新冠肺炎特异性抗病毒疗法的开发。

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.