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：
10463664
负责人：
Kyeong-Ok Chang
金额：
$ 73.5万
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/10463664
关键词：
2019-nCoV ACE2 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 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 Respiratory Disease Risk Roentgen Rays SARS coronavirus SARS-CoV-2 genome SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 protease Series Structure Structure-Activity Relationship Therapeutic Time Transgenic Organisms Upper Respiratory Infections Vaccines Viral Virus Virus Replication analog anti-viral efficacy antiviral drug development base clinical candidate clinical development clinical efficacy design drug candidate drug development efficacy study human coronavirus improved in vivo indexing inhibitor lead optimization lead series mouse model novel pre-clinical preclinical study receptor respiratory scaffold screening small molecule inhibitor therapy development

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.

项目摘要人类冠状病毒通常会引起普通感冒，一种轻度的上呼吸道疾病，但是全球周期从动物。其中包括严重的急性呼吸道冠状病毒（SARS-COV），中东呼吸综合征冠状病毒（MERS-COV）和最近的SARS-COV-2，是冠状病毒疾病2019的致病药物（新冠肺炎）。目前，没有针对这些病毒的持牌疫苗或抗病毒药物，强调了迫切需要针对冠状病毒采取预防和治疗措施。新冠病毒基因组编码大型多蛋白，这些多蛋白质由3C样蛋白酶（3ClPro）和类木瓜蛋白酶样处理蛋白酶。这两种蛋白酶对于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靶标。我们在这一领域的尝试导致发现了多种病毒的广谱抑制剂，包括编码3CLPRO的冠状病毒和诺病毒，以及第一次证明临床功效猫冠状病毒3CLPRO抑制剂。最近，我们证明了一系列二肽基有效抑制人类冠状病毒，包括细胞培养中的MERS-COV和SARS-COV-2，并在体内显示 MERS-COV感染的DPP4-KI小鼠模型中的功效。化合物的抗病毒靶通过从SARS-COV，SARS-获得高分辨率晶体结构3Clpro抑制剂复合物验证 COV-2和MERS-COV。我们在本文中假设确定的系列可以用作 SARS-COV-2特异性抗病毒药的发展。拟议研究的直接和总体目标是为了进一步优化SARS-COV-2的鉴定铅抑制剂的药理活性PK参数 3Clpro和针对SARS-COV-2的体内功效的演示。我们研究的预期结果是临床前候选者（和1-2个备用化合物）的选择非常适合进一步进行临床前研究，最终导致了共证特异性抗病毒治疗的发展。