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

针对 SARS-CoV-2 3C 样蛋白酶的小分子抑制剂

基本信息

批准号：
10238615
负责人：
Kyeong-Ok Chang
金额：
$ 77.4万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10238615
关键词：
2019-nCoV ACE2 Acute Adenoviruses Adopted Animal Model Animals Antiviral Agents Area Back Binding Biochemical Biological Assay COVID-19 COVID-19 susceptibility COVID-19 treatment Cell Culture Techniques Cells Chemicals China Common Cold Complex Coronavirus Coronavirus Infections Crystallization Development Disease Disease Outbreaks Drug Design Drug Targeting Elements Enzymes Family Feline Coronavirus Genome Goals Histopathology Human In Vitro K-18 conjugate Knock-in Knock-in Mouse Lead Lung Lung diseases Measures Middle East Respiratory Syndrome Coronavirus Modeling Molecular Conformation Mus Norovirus Outcome Papain Pathogenicity Peptide Hydrolases Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Polyproteins Preventive Process Protease Inhibitor Public Health RNA Viruses Research Resolution Risk Roentgen Rays SARS coronavirus SARS-CoV-2 genome SARS-CoV-2 infection SARS-CoV-2 inhibitor Series Structure Structure-Activity Relationship Therapeutic Time Transgenic Organisms Upper Respiratory Infections Vaccines Viral Virus Virus Replication analog anti-viral efficacy base clinical candidate clinical development clinical efficacy design drug candidate drug development efficacy study human coronavirus improved in vivo indexing inhibitor/antagonist lead optimization lead series mouse model novel pre-clinical preclinical study receptor respiratory scaffold screening small molecule inhibitor therapy development virology

项目摘要

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.

项目概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，但在全球范围内新型人类冠状病毒感染并导致严重呼吸道疾病的爆发定期出现动物。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，还没有针对这些病毒的许可疫苗或抗病毒药物，这凸显了迫切需要制定针对冠状病毒的预防和治疗措施。新冠病毒基因组编码大的多蛋白，这些蛋白由 3C 样蛋白酶 (3CLpro) 和木瓜蛋白酶样加工蛋白酶。这两种蛋白酶对于病毒复制至关重要，使其成为药物开发的有吸引力的靶标。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，以及首次证明临床疗效猫冠状病毒 3CLpro 抑制剂。最近，我们证明了二肽基系列化合物在细胞培养物中有效抑制人类冠状病毒，包括 MERS-CoV 和 SARS-CoV-2，并在体内展示在 MERS-CoV 感染的 DPP4-KI 小鼠模型中的疗效。该化合物的抗病毒靶点是通过从 SARS-CoV、SARS-CoV 获得高分辨率晶体结构 3CLpro-抑制剂复合物进行验证冠状病毒-2 和中东呼吸综合征冠状病毒。我们在此假设所确定的系列可以作为 SARS-CoV-2 特异性抗病毒药物的开发。拟议研究的直接和总体目标是进一步优化已确定的 SARS-CoV-2 先导抑制剂的药理活性 PK 参数 3CLpro 以及针对 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一步进行的临床前候选化合物（和 1-2 种备用化合物）临床前研究，最终导致开发出针对 COVID-19 的抗病毒疗法。