Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections

小分子 E6 抑制剂治疗 HPV 感染引起的发育异常

基本信息

  • 批准号:
    10390563
  • 负责人:
  • 金额:
    $ 29.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Human papillomaviruses (HPV) cause exceedingly common infections of cutaneous and mucosal epithelia. Infection with specific “high risk” HPV genotypes can progress to pre- malignant lesions called dysplasias, which over a period of years, can eventuate in invasive and metastatic epithelial malignancies. Our therapeutic goal is to treat early stage infections of the cervix, genitalia, and anus that afflict millions of women and men before these progress to invasive cancers. Kovina Therapeutics strategy is to eliminate HPV infection by selectively targeting the E6 protein and preventing interactions with its cellular binding partners. E6 is necessary for viral genome replication and maintenance and is always expressed in HPV-associated dysplasia and malignancies. We performed in silico screening of chemical libraries for small molecules that would resemble the interface of E6 with several of its cellular partners. Our assays focused on the protein-protein interaction of E6 with the ubiquitin ligase E6AP, which mediates ubiquitination and proteasome mediated destruction of the tumor suppressor protein p53. Using this model, we designed and synthesized compounds that 1) bind to HPV-16 E6 and 2) are armed with a ‘warhead’ to make a covalent bond with a specific cysteine in HPV-16 E6 binding pocket for E6AP. The approach to identify molecules equipped with reactive warheads that mediate covalent and irreversible binding to cysteine is exemplified in several new clinically available drugs that target proteins previously considered undruggable. We discovered several compounds covalently bound to E6 via this cysteine residue, block E6 interaction with E6AP, restore P53 function, and induce death of HPV-16 expressing cells. Multiple biochemical analyses including X-ray crystallography prove these inhibitors occupy the targeted E6 pocket and form a single adduct with this cysteine. Iterative optimization guided by the co-crystal data enabled design and synthesis of >80 novel compounds and has resulted chemotypes with increased activity. This one-year Phase I SBIR proposal plans to screen our existing E6 inhibitor collection to determine their biological activities in cell-based assays and pharmacokinetic properties that would meet FDA guidelines for a topical agent. We will initiate drug development studies including formulation for topical application and early stage pharmacokinetic and toxicology characterization. The success of Phase I study will validate this antiviral strategy and position us to proceed to apply for a Phase II SBIR to perform IND-enabling studies.
人乳头瘤病毒(HPV)引起极为常见的皮肤和皮肤感染

项目成果

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ELLIOT J. ANDROPHY其他文献

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{{ truncateString('ELLIOT J. ANDROPHY', 18)}}的其他基金

Small Molecule E6 Inhibitors to Treat Oropharyngeal Cancers Caused by HPV Infections
小分子 E6 抑制剂治疗 HPV 感染引起的口咽癌
  • 批准号:
    10484043
  • 财政年份:
    2022
  • 资助金额:
    $ 29.85万
  • 项目类别:
Development of a mouse model to test HPV Antiviral compounds
开发小鼠模型来测试 HPV 抗病毒化合物
  • 批准号:
    10582890
  • 财政年份:
    2022
  • 资助金额:
    $ 29.85万
  • 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
  • 批准号:
    10220227
  • 财政年份:
    2021
  • 资助金额:
    $ 29.85万
  • 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
  • 批准号:
    10610388
  • 财政年份:
    2021
  • 资助金额:
    $ 29.85万
  • 项目类别:
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
  • 批准号:
    10397131
  • 财政年份:
    2021
  • 资助金额:
    $ 29.85万
  • 项目类别:
Optimization of a novel series of thiazolopyridines for the treatment of SMA
用于治疗 SMA 的新型噻唑并吡啶系列的优化
  • 批准号:
    8892548
  • 财政年份:
    2015
  • 资助金额:
    $ 29.85万
  • 项目类别:
Toward drug treatment of spinal muscular atrophy: Mechanism of action
脊髓性肌萎缩症的药物治疗:作用机制
  • 批准号:
    8823350
  • 财政年份:
    2014
  • 资助金额:
    $ 29.85万
  • 项目类别:
The COPA vesicle protein and pathogenesis of spinal muscular atrophy
COPA囊泡蛋白与脊髓性肌萎缩症发病机制
  • 批准号:
    8866202
  • 财政年份:
    2013
  • 资助金额:
    $ 29.85万
  • 项目类别:
The Indiana Cutaneous Biological Research Training Program
印第安纳州皮肤生物学研究培训计划
  • 批准号:
    8827676
  • 财政年份:
    2013
  • 资助金额:
    $ 29.85万
  • 项目类别:
The COPA vesicle protein and pathogenesis of spinal muscular atrophy
COPA囊泡蛋白与脊髓性肌萎缩症发病机制
  • 批准号:
    10612848
  • 财政年份:
    2013
  • 资助金额:
    $ 29.85万
  • 项目类别:

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开发新一代抗病毒药物,可有效对抗耐药病毒并预防严重疾病和后遗症。
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