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

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
负责人:
Shiqing Xu
金额:
$22.19万
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
项目状态:
已结题
起止时间:
2021-06-25 至 2023-05-31

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中文摘要
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英文摘要
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.
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Development of PROTACs Targeting Papain-like Protease as Broad-Spectrum Anti-Coronavirus Therapeutics
  • 批准号:
    10527571
  • 项目类别:
  • 资助金额:
    $22.18万
  • 财政年份:
    2022
  • 负责人:
    Shiqing Xu
  • 依托单位:
Development of PROTACs Targeting Papain-like Protease as Broad-Spectrum Anti-Coronavirus Therapeutics
  • 批准号:
    10629364
  • 项目类别:
  • 资助金额:
    $18.37万
  • 财政年份:
    2022
  • 负责人:
    Shiqing Xu
  • 依托单位:
The Development of Reversible Covalent PROTAC Technology as a New Anti-COVID-19 Strategy
  • 批准号:
    10437885
  • 项目类别:
  • 资助金额:
    $18.38万
  • 财政年份:
    2021
  • 负责人:
    Shiqing Xu
  • 依托单位:
海外基金