The Development of Reversible Covalent PROTAC Technology as a New Anti-COVID-19 Strategy

可逆共价 PROTAC 技术的发展作为新的抗 COVID-19 策略

• 批准号: 10437885
• 负责人: Shiqing Xu
• 金额: $ 18.38万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-25 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437885
• 关键词: 2019-nCoV; Active Sites; Address; Affinity; Binding; Binding Sites; COVID-19; COVID-19 pandemic; COVID-19 treatment; Caspase; Cells; Cessation of life; Chimera organism; Chimeric Proteins; Complex; Coronavirus; Crystallization; Crystallography; Data; Development; Disadvantaged; Dose-Limiting; Drug Targeting; Drug resistance; Emerging Technologies; Evaluation; Event; Exhibits; Flow Cytometry; Fluorescence; Goals; Infection; Lead; Lentivirus; Ligand Binding; Ligands; Measures; Mutation; Nature; Peptide Hydrolases; Pharmaceutical Preparations; Property; Protease Inhibitor; Proteins; RNA Viruses; Reporting; Research; Resistance; SARS coronavirus; Severe Acute Respiratory Syndrome; Site; Structure; System; Technology; Time; Toxic effect; Ubiquitination; Vaccines; Viral; Viral Pathogenesis; Viral Proteins; Virus Replication; Work; antiviral drug development; base; cellular development; combat; design; drug discovery; global health emergency; improved; inhibitor; innovation; nanomolar; novel strategies; overexpression; pandemic disease; pathogen; preclinical evaluation; protein degradation; protein protein interaction; recruit; small molecule; targeted treatment; technology development; tool; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT The current COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. However, to date, no effective targeted drug or vaccine has been identified yet. Finding effective targeted treatment options is of paramount importance. SARS-CoV-2 is an enveloped, positive-sensed RNA virus. Main protease (Mpro), a cysteine protease, is essential for viral replication and pathogenesis which represents an attractive target for the development of antiviral drugs against SARS-CoV-2. One of the traditional antiviral strategies is to develop high- affinity ligands that bind directly to viral proteins and inhibit their functions like SARS-CoV-2 Mpro (SC2Mpro). However, these occupancy-driven inhibitors may lead to several potential problems such as off-target toxicity, dose-limiting toxicity, and drug resistance. Thus, there is an urgent need for new antiviral strategies that can address these challenges by exploiting alternative mechanisms to combat existing CoV pathogens like SARS- CoV-2. Proteolytic targeting chimaera (PROTAC) is an emerging technology for targeted protein degradation in drug discovery. PROTACs are event-driven bifunctional small molecules that simultaneously engage an E3 ubiquitin ligase and a target protein to facilitate the formation of a ternary complex, leading to the ubiquitination and ultimate degradation of the target protein. PROTACs have many potential advantages compared to traditional occupancy-based inhibitors, including (i) catalytic nature to allow for sub-stoichiometric activity, (ii) enhanced target selectivity, (iii) high barrier to resistance; and (iv) abrogating all functions of the target protein and its downstream proteins. On this basis, this proposal provides an innovative anti-CoV strategy: reversible covalent PROTACs by combination of the advantages of ultra-potent reversible covalent SC2Mpro inhibitors and event-driven PROTAC technology. The overall goal is to validate degradation of SC2Mpro as a new strategy for developing COVID-19 drugs with improved selectivity and efficacy. The current proposal is built upon the preliminary work on the discovery of several potent reversible covalent SC2Mpro inhibitors (lowest IC50 < 10 nM) and one small-molecule SC2Mpro PROTAC degrader. Encouraged by these exciting preliminary studies, the goal will be achieved by pursuing the following aims: (1) the development of cellular systems to evaluate degradation of SC2Mpro; (2) the development of various potent reversible covalent anti-CoV PROTACs targeting SC2Mpro; (3) the exploration of the relationship between SC2Mpro degradation potencies and anti-SARS-CoV-2 activities of reversible covalent anti-CoV PROTACs. The successful completion of the proposed study will not only lead to potent anti-CoV PROTACs with good drug-like properties that can be potentially advanced to pre-clinical evaluation for treating COVID-19, but also will provide a proof-of-concept study for more broadly developing anti- CoV PROTACs against various coronaviruses.

项目摘要/摘要 由SARS-COV-2引起的当前的Covid-19-19是全球卫生紧急情况。但是，迄今为止， 尚未确定有效的靶向药物或疫苗。寻找有效的目标治疗选择是 最重要的重要性。 SARS-COV-2是一种包膜，阳性的RNA病毒。主蛋白酶（MPRO），a 半胱氨酸蛋白酶，对于病毒复制和发病机理至关重要，这代表了吸引人的目标 开发针对SARS-COV-2的抗病毒药物。传统的抗病毒策略之一是发展高 亲和力配体直接与病毒蛋白结合并抑制其功能，例如SARS-COV-2 MPRO（SC2MPRO）。 但是，这些以占用率驱动的抑制剂可能会导致几个潜在的问题，例如脱靶毒性， 剂量限制毒性和耐药性。因此，迫切需要新的抗病毒策略可以 通过利用替代机制来应对现有的COV病原体（如SARS）来应对这些挑战 COV-2。蛋白水解靶向嵌合体（Protac）是针对靶向蛋白质降解的新兴技术 药物发现。 Protac是事件驱动的双功能小分子，同时参与E3 泛素连接酶和靶蛋白，以促进三元复合物的形成，导致泛素化 目标蛋白的最终降解。与 传统的基于占用率的抑制剂，包括（i）催化性质以进行亚化学计量活动，（ii） 提高目标选择性，（iii）高阻力障碍； （iv）废除目标蛋白的所有功能 及其下游蛋白质。在此基础上，该提案提供了一种创新的反COV策略：可逆 通过超功能可逆的共价SC2MPRO抑制剂和 事件驱动的Protac技术。总体目标是验证SC2MPRO的退化作为新的策略 开发具有提高选择性和疗效的COVID-19-19种药物。当前的提议建立在 关于发现几种有效可逆共价SC2MPRO抑制剂的初步工作（最低IC50 <10 nm） 和一个小分子SC2MPRO PROTAC降解器。在这些令人兴奋的初步研究的鼓励下，目标 将通过追求以下目标来实现：（1）蜂窝系统评估降解的发展 sc2mpro; （2）靶向SC2MPRO的各种有效可逆共价抗COV prota的发展； （3） 探索SC2MPro降解效力与反SARS-COV-2活动之间的关系 可逆的共价抗COV Protac。拟议研究的成功完成不仅会导致 具有良好药物样特性的有效抗COV protac，可以潜在地前进到临床前 评估COVID-19，但也将提供概念验证研究，以更广泛地发展 COV Protac针对各种冠状病毒。

项目成果

A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease.

SARS-CoV-2 主要蛋白酶的可逆共价二肽基抑制剂的系统调查。

• DOI: 10.1021/acs.jmedchem.3c00221
• 发表时间: 2023
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Geng,ZhiZachary;Atla,Sandeep;Shaabani,Namir;Vulupala,Veerabhadra;Yang,KaiS;Alugubelli,YugendarR;Khatua,Kaustav;Chen,Peng-Hsun;Xiao,Jing;Blankenship,LaurenR;Ma,XinyuR;Vatansever,ErolC;Cho,Chia-ChuanD;Ma,Yuying;Allen,Robe
• 通讯作者: Allen,Robe

A systematic exploration of boceprevir-based main protease inhibitors as SARS-CoV-2 antivirals.

• DOI: 10.1016/j.ejmech.2022.114596
• 发表时间: 2022-10-05
• 期刊: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 6.7
• 作者: Alugubelli, Yugendar R.;Geng, Zhi Zachary;Yang, Kai S.;Shaabani, Namir;Khatua, Kaustav;Ma, Xinyu R.;Vatansever, Erol C.;Cho, Chia-Chuan;Ma, Yuying;Xiao, Jing;Blankenship, Lauren R.;Yu, Ge;Sankaran, Banumathi;Li, Pingwei;Allen, Robert;Ji, Henry;Xu, Shiqing;Liu, Wenshe Ray
• 通讯作者: Liu, Wenshe Ray

A multi-pronged evaluation of aldehyde-based tripeptidyl main protease inhibitors as SARS-CoV-2 antivirals.

• DOI: 10.1016/j.ejmech.2022.114570
• 发表时间: 2022-10-05
• 期刊: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 6.7
• 作者: Ma, Yuying;Yang, Kai S.;Geng, Zhi Zachary;Alugubelli, Yugendar R.;Shaabani, Namir;Vatansever, Erol C.;Ma, Xinyu R.;Cho, Chia-Chuan;Khatua, Kaustav;Xiao, Jing;Blankenship, Lauren R.;Yu, Ge;Sankaran, Banumathi;Li, Pingwei;Allen, Robert;Ji, Henry;Xu, Shiqing;Liu, Wenshe Ray
• 通讯作者: Liu, Wenshe Ray

Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay.

• DOI: 10.1021/acscentsci.1c00910
• 发表时间: 2022-02-23
• 期刊: ACS central science
• 影响因子: 18.2
• 作者: Cao W;Cho CD;Geng ZZ;Shaabani N;Ma XR;Vatansever EC;Alugubelli YR;Ma Y;Chaki SP;Ellenburg WH;Yang KS;Qiao Y;Allen R;Neuman BW;Ji H;Xu S;Liu WR
• 通讯作者: Liu WR