Broad-spectrum therapeutics against SARS-CoV-2 3CL protease

针对 SARS-CoV-2 3CL 蛋白酶的广谱疗法

• 批准号: 10675510
• 负责人: ELIZABETH ANN FITZPATRICK
• 金额: $ 64.82万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675510
• 关键词: 2019-nCoV; Acids; Acute Respiratory Distress Syndrome; Affinity; Animal Model; Animals; Anosmia; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Therapy; Binding; Biological Assay; Biological Availability; COVID-19; COVID-19 prevention; COVID-19 therapeutics; COVID-19 treatment; Cell Culture Techniques; Cells; Characteristics; China; Coronavirus; Coronavirus Infections; Coughing; Cytochrome P450; Data; Dexamethasone; Diarrhea; Disease; Docking; Drug Design; Drug Kinetics; Drug resistance; Dryness; Early treatment; Enterovirus; Enzyme Inhibition; Enzymes; Excretory function; Exhibits; Fever; Glycoproteins; Goals; Healthcare Systems; Hybrids; In Vitro; Investigational New Drug Application; Lead; Libraries; Ligands; Liver Microsomes; Lung; Mesocricetus auratus; Metabolism; Modeling; Molecular; Norovirus; Oral; Outcome; Pathogenicity; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pneumonia; Polyproteins; Prevention; Preventive; Prophylactic treatment; Protease Inhibitor; Province; Recombinant Proteins; Resistance; Ritonavir; SARS-CoV-2 antiviral; SARS-CoV-2 inhibitor; Serum; Shortness of Breath; Speed; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Index; Toxic effect; Treatment Efficacy; Vaccines; Viral; Viral Physiology; Viral Proteins; Viremia; Virus; Virus Inhibitors; Virus Replication; Work; X-Ray Crystallography; absorption; analog; antiviral drug development; aqueous; clinical development; common symptom; coronavirus pandemic; cytotoxicity; design; drug candidate; drug discovery; efficacy evaluation; efficacy testing; human coronavirus; inhibitor; lead optimization; meter; molecular modeling; nanomolar; nonhuman primate; nucleoside analog; pandemic disease; pandemic impact; peptidomimetics; pharmacophore; preclinical study; programs; prophylactic; remdesivir; screening; small molecule; small molecule inhibitor; targeted agent; virtual; virtual screening

PROJECT SUMMARY/ABSTRACT COVID-19 was first identified in December 2019 in Wuhan, Hubei province, China, resulting in the ongoing 2019- 2020 pandemic. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 2). Common symptoms of the disease include fever, dry cough, shortness of breath, diarrhea, and loss of smell. Complications may include pneumonia, viral sepsis, and acute respiratory distress syndrome. As of today, other than remdesivir, there is no approved small molecule drug for the treatment of COVID-19 and the discovery of an effective vaccine remains uncertain. Our long-term goal is to develop antiviral drugs for the treatment of COVID-19 and human coronavirus infections in general. Our central hypothesis is that inhibition of SARS-CoV- 2 polyprotein cleavage results in the prevention and early treatment of COVID-19 before it progresses to its more severe form. We will identify nanomolar inhibitors of the CoV 3C-like protease (3CLpro) suitable to be developed as antiviral agents for the treatment of COVID-19 and other coronavirus infections. The proposal targets the 3CLpro, a key enzyme for SARS-CoV-2 polyprotein cleavage and viral replication. Our overall premise is that small molecule inhibitors targeting this essential viral enzyme will inhibit replication, and therefore have the potential to be of both preventive and therapeutic value. Thus, our primary objective is to design and develop structure-based small-molecule inhibitors targeting coronavirus 3CLpro using our established and proven drug discovery expertise. Guided by strong preliminary data, the inhibition of polyprotein cleavage hypothesis will be tested by pursuing three specific aims: Aim 1) To inhibit SARS-CoV-2 polyprotein cleavage by developing covalent peptidic inhibitors of 3CLpro (nsp5).; Aim 2) To inhibit SARS-CoV-2 polyprotein cleavage by developing noncovalent nonpeptidic inhibitors of 3CLpro (nsp5).; and Aim 3) To determine the efficacy of covalent and noncovalent SARS-CoV-2 3CLpro inhibitors in a golden hamster model. Under the first aim, lead compound 3150 and its analogs will be tested in viral and enzyme assays for inhibitory activity of SARS-CoV-2 3CLpro. An aqueous soluble form of 3150 will be evaluated in the animal model. Structure-based drug design approaches will be employed to optimize 3150 for binding to the crystal structure of SARS-CoV-2 3CLpro. Under aim 2, Structure-based virtual screening and hybrid ligand screening approaches along with medicinal chemistry will be used to prepare and evaluate noncovalent nonpeptidic inhibitors of 3CLpro. Under the third aim, top-ranked SARS-CoV-2 3CLpro covalent and noncovalent inhibitors will be tested for pharmacokinetics and efficacy in a golden hamster COVID-19 model. The ultimate goal of the proposed studies is to advance an anti-COVID-19 drug candidate to the stage of filing an investigational new drug (IND) application. Overall, the results of this project will have a significant positive impact because they lay the groundwork for the clinical development of COVID-19 antiviral therapy and the potential to combine a potent and selective protease inhibitor with a nucleoside analog (e.g., remdesivir) and if needed anti-inflammatory drugs (e.g., dexamethasone or baricitinib).

项目摘要/摘要 COVID-19于2019年12月在中国湖北省的武汉最初确定，导致了2019年的持续 2020年大流行。 COVID-19是由严重的急性呼吸综合征冠状病毒2（SARS-COV-）引起的 2）。疾病的常见症状包括发烧，干咳嗽，呼吸急促，腹泻和气味降低。 并发症可能包括肺炎，病毒败血症和急性呼吸窘迫综合征。截至今天，其他 比Remdesivir，没有批准的小分子药物用于治疗Covid-19和发现 有效的疫苗仍然不确定。我们的长期目标是开发用于治疗的抗病毒药物 Covid-19和人类冠状病毒感染总体上。我们的中心假设是抑制SARS-COV- 2多蛋白裂解导致预防和早期治疗Covid-19，然后才能发展到更多 严重的形式。我们将确定适合开发的COV 3C样蛋白酶（3CLPRO）的纳摩尔抑制剂 作为治疗Covid-19和其他冠状病毒感染的抗病毒剂。该提议针对 3Clpro，一种用于SARS-COV-2多蛋白裂解和病毒复制的关键酶。我们的总体前提是 针对这种必需病毒酶的小分子抑制剂将抑制复制，因此具有 具有预防和治疗价值的潜力。因此，我们的主要目标是设计和开发 基于结构的小分子抑制剂靶向冠状病毒3CLPRO使用我们已建立的验证药物 发现专业知识。在强大的初步数据的指导下，多蛋白裂解假设的抑制作用将是 通过追求三个特定目标测试：目标1）通过开发抑制SARS-COV-2多蛋白裂解 3Clpro（NSP5）的共价肽抑制剂。目标2）通过开发抑制SARS-COV-2多蛋白裂解 3Clpro（NSP5）的非共价非肽抑制剂。目标3）确定共价和 金仓鼠模型中的非共价SARS-COV-2 3CLPRO抑制剂。在第一个目标下，铅大院 3150及其类似物将在病毒和酶测定中测试SARS-COV-2 3CLPRO的抑制活性。一个 在动物模型中将评估3150的可溶性形式。基于结构的药物设计方法 将采用优化3150与SARS-COV-2 3CLPRO的晶体结构结合。在AIM 2下， 基于结构的虚拟筛查和混合配体筛选方法以及药物化学将 用于制备和评估3Clpro的非共价非肽抑制剂。在第三个目标下，排名 SARS-COV-2 3CLPRO共价和非共价抑制剂将在A中测试药代动力学和功效 黄金仓鼠Covid-19型号。拟议的研究的最终目标是促进抗卵石19 候选药物的阶段提交研究新药（IND）。总体而言，结果 项目将产生重大的积极影响，因为它们为临床发展奠定了基础 COVID-19抗病毒疗法以及将有效和选择性蛋白酶抑制剂与A相结合的潜力 核苷类似物（例如，remdesivir）和抗炎药（例如，地塞米松或巴西替尼）。

项目成果

Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities.

• DOI: 10.1021/acs.jmedchem.2c01242
• 发表时间: 2023-02
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Pritam Maity;Joydeep Chatterjee;Kiran T Patil;Sahil Arora;Madhurendra K Katiyar;Manvendra Kumar;Amirreza Samarbakhsh;G. Joshi;Priyadeep Bhutani;M. Chugh;Navnath S. Gavande;Raj Kumar

PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy.

• DOI: 10.1186/s12943-022-01707-5
• 发表时间: 2023-03-30
• 期刊: MOLECULAR CANCER
• 影响因子: 37.3
• 作者: Kelm, Jeremy M. M.;Pandey, Deepti S. S.;Malin, Evan;Kansou, Hussein;Arora, Sahil;Kumar, Raj;Gavande, Navnath S. S.
• 通讯作者: Gavande, Navnath S. S.

Assessment of a Computational Approach to Predict Drug Resistance Mutations for HIV, HBV and SARS-CoV-2.

• DOI: 10.3390/molecules27175413
• 发表时间: 2022-08-24
• 期刊: MOLECULES
• 影响因子: 4.6
• 作者: Patel, Dharmeshkumar;Ono, Suzane K.;Bassit, Leda;Verma, Kiran;Amblard, Franck;Schinazi, Raymond F.
• 通讯作者: Schinazi, Raymond F.

Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease.

冠状病毒3C样蛋白酶的新型拟肽抑制剂的合成及生物学评价。

• DOI: 10.1016/j.ejmech.2024.116263
• 发表时间: 2024
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Amblard,Franck;LeCher,JuliaC;De,Ramyani;Zhou,Shaoman;Liu,Peng;Goh,ShuLing;Tao,Sijia;Patel,Dharmeshkumar;Downs-Bowen,Jessica;Zandi,Keivan;Zhang,Huanchun;Chaudhry,Gitika;McBrayer,Tamara;Muczynski,Michael;Al-Homoudi,Abdullah;E
• 通讯作者: E