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

基本信息

  • 批准号:
    10437885
  • 负责人:
  • 金额:
    $ 18.38万
  • 依托单位:
  • 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:
    2021-06-25 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

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.
项目概要/摘要 当前由 SARS-CoV-2 引起的 COVID-19 大流行是全球卫生紧急事件。然而,迄今为止, 目前尚未发现有效的靶向药物或疫苗。寻找有效的靶向治疗方案至关重要 至关重要。 SARS-CoV-2 是一种有包膜的阳性 RNA 病毒。主要蛋白酶 (Mpro) 半胱氨酸蛋白酶对于病毒复制和发病机制至关重要,是一个有吸引力的靶标 开发针对 SARS-CoV-2 的抗病毒药物。传统的抗病毒策略之一是开发高 亲和配体直接与病毒蛋白结合并抑制其功能,如 SARS-CoV-2 Mpro (SC2Mpro)。 然而,这些占用驱动的抑制剂可能会导致一些潜在的问题,例如脱靶毒性、 剂量限制性毒性和耐药性。因此,迫切需要新的抗病毒策略 通过利用替代机制来对抗现有的冠状病毒病原体(如 SARS)来应对这些挑战 冠状病毒-2。蛋白水解靶向嵌合体 (PROTAC) 是一种新兴技术,用于靶向蛋白质降解 药物发现。 PROTAC 是事件驱动的双功能小分子,同时与 E3 结合 泛素连接酶和靶蛋白促进三元复合物的形成,从而实现泛素化 以及目标蛋白的最终降解。与相比,PROTAC 具有许多潜在优势 传统的基于占用的抑制剂,包括(i)催化性质以实现亚化学计量活性,(ii) 增强的靶标选择性,(iii) 高耐药性; (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抗冠状病毒策略:可逆 共价 PROTAC 结合了超强可逆共价 SC2Mpro 抑制剂和 事件驱动的 PROTAC 技术。总体目标是验证 SC2Mpro 的降级作为一种新策略 开发具有更高选择性和功效的 COVID-19 药物。目前的提案是建立在 发现几种有效可逆共价 SC2Mpro 抑制剂的初步工作(最低 IC50 < 10 nM) 和一种小分子 SC2Mpro PROTAC 降解剂。受到这些令人兴奋的初步研究的鼓舞,目标 将通过追求以下目标来实现:(1)开发评估退化的细胞系统 SC2Mpro; (2) 开发多种针对 SC2Mpro 的强效可逆共价抗 CoV PROTAC; (3) 探索 SC2Mpro 降解效力与抗 SARS-CoV-2 活性之间的关系 可逆共价抗 CoV PROTAC。拟议研究的成功完成不仅将导致 有效的抗冠状病毒 PROTAC 具有良好的药物特性,有可能进入临床前阶段 评估治疗 COVID-19,同时也将为更广泛地开发抗病毒药物提供概念验证研究 针对各种冠状病毒的 CoV PROTAC。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 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:
  • 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:
  • 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:
  • 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
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Shiqing Xu其他文献

Shiqing Xu的其他文献

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{{ truncateString('Shiqing Xu', 18)}}的其他基金

Development of PROTACs Targeting Papain-like Protease as Broad-Spectrum Anti-Coronavirus Therapeutics
开发针对木瓜蛋白酶的 PROTAC 作为广谱抗冠状病毒治疗药物
  • 批准号:
    10527571
  • 财政年份:
    2022
  • 资助金额:
    $ 18.38万
  • 项目类别:
Development of PROTACs Targeting Papain-like Protease as Broad-Spectrum Anti-Coronavirus Therapeutics
开发针对木瓜蛋白酶的 PROTAC 作为广谱抗冠状病毒治疗药物
  • 批准号:
    10629364
  • 财政年份:
    2022
  • 资助金额:
    $ 18.38万
  • 项目类别:
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:
    10289017
  • 财政年份:
    2021
  • 资助金额:
    $ 18.38万
  • 项目类别:

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宿主与 SARS-CoV-2 之间的战斗中病毒基因调控的新机制
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