Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

开发基于 4-(芳酰氨基)哌啶的进入抑制剂作为抗流感疗法

基本信息

  • 批准号:
    10618383
  • 负责人:
  • 金额:
    $ 99.94万
  • 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:
    2021-04-02 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Influenza A viruses belong to the orthomyxoviridae family, and have a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least six months to develop. Furthermore, vaccination has limited effectiveness in the treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the neuraminidase inhibitors (NAIs; oseltamivir, zanamivir and peramivir), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not now recommended since all of the circulating influenza strains have acquired resistance. (Xofluza, a polymerase acidic endonuclease inhibitor, has just been approved in 2018 and is yet untried during a flu season.) The rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggests that NAIs alone may not be sufficient as effective therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses, with IC50 values in the nanomolar range. We have synthesized structurally diverse analogs of the anti-influenza hit series using structure-activity relationships (SARs) to improve potency and selectivity; validated the lead inhibitor candidates in the infectious assay and investigated the mechanism of action (MOA) of the these inhibitors; and selected anti-influenza inhibitors with excellent in vitro potency and selectivity values and druglike in vivo pharmacokinetic properties. In this Fast Track STTR Phase I &II application, we propose four specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of the advanced lead compounds with HA proteins; (3) evaluate the pharmacokinetics/toxicokinetics of the advanced lead compounds; and (4) preclinical development.
甲型流感病毒属于正黏液病毒科,具有负义的分段RNA

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Lijun Rong其他文献

Lijun Rong的其他文献

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{{ truncateString('Lijun Rong', 18)}}的其他基金

Optimizing Ridaifen-B analogs as potential therapeutics for Ebola viruses
优化 Ridaifen-B 类似物作为埃博拉病毒的潜在疗法
  • 批准号:
    10586633
  • 财政年份:
    2022
  • 资助金额:
    $ 99.94万
  • 项目类别:
Optimizing Ridaifen-B analogs as potential therapeutics for Ebola viruses
优化 Ridaifen-B 类似物作为埃博拉病毒的潜在疗法
  • 批准号:
    10708178
  • 财政年份:
    2022
  • 资助金额:
    $ 99.94万
  • 项目类别:
Furopyrimidines as novel inhibitors of henipaviruses
呋喃嘧啶作为亨尼帕病毒的新型抑制剂
  • 批准号:
    10327725
  • 财政年份:
    2021
  • 资助金额:
    $ 99.94万
  • 项目类别:
Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics
开发基于 4-(芳酰氨基)哌啶的进入抑制剂作为抗流感疗法
  • 批准号:
    10576494
  • 财政年份:
    2021
  • 资助金额:
    $ 99.94万
  • 项目类别:
Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics
开发基于 4-(芳酰氨基)哌啶的进入抑制剂作为抗流感疗法
  • 批准号:
    10256145
  • 财政年份:
    2021
  • 资助金额:
    $ 99.94万
  • 项目类别:
Development of group 2 influenza A virus entry inhibitors
2 组甲型流感病毒侵入抑制剂的开发
  • 批准号:
    9903216
  • 财政年份:
    2019
  • 资助金额:
    $ 99.94万
  • 项目类别:
4-(Aminomethyl) benzamides as novel anti-Ebola agents
4-(氨甲基)苯甲酰胺作为新型抗埃博拉药物
  • 批准号:
    10207381
  • 财政年份:
    2016
  • 资助金额:
    $ 99.94万
  • 项目类别:
4-Aminopiperidines as novel anti-influenza agents
4-氨基哌啶作为新型抗流感药物
  • 批准号:
    9277398
  • 财政年份:
    2016
  • 资助金额:
    $ 99.94万
  • 项目类别:
GPCR antagonists as anti-Ebola virus entry inhibitors
GPCR 拮抗剂作为抗埃博拉病毒进入抑制剂
  • 批准号:
    8980076
  • 财政年份:
    2015
  • 资助金额:
    $ 99.94万
  • 项目类别:
GPCR antagonists as anti-Ebola virus entry inhibitors
GPCR 拮抗剂作为抗埃博拉病毒进入抑制剂
  • 批准号:
    9090033
  • 财政年份:
    2015
  • 资助金额:
    $ 99.94万
  • 项目类别:

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