HTS Targeting HIV-1 Protease Autoprocessing for First in Class Drug Discovery
HTS 靶向 HIV-1 蛋白酶自动处理以实现一流药物发现
基本信息
- 批准号:9919988
- 负责人:
- 金额:$ 80.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAntiviral AgentsBindingBiochemicalBiologicalBiological AssayBiological SciencesCatalogsCatalytic DomainCellsChemicalsCollaborationsCollectionDrug DesignDrug resistanceEnzyme-Linked Immunosorbent AssayEnzymesFDA approvedFractionationGeneticGoalsHIVHIV-1HIV-1 proteaseInstitutesLeadLifeLongevityMediatingMedicalMichiganMicrobeMolecular ConformationMutationNatural ProductsPatientsPeptide HydrolasesPerformancePhenotypePredispositionProcessProductionProtease InhibitorProteolysisRNA-Directed DNA PolymeraseReactionReportingResistanceSagittariaStructureTechnologyTherapeuticTherapeutic AgentsTimeTreatment EfficacyUniversitiesViralVirionanalogantiretroviral therapyassay developmentbasecombatdrug discoveryfollow-uphigh throughput screeningimprovedinhibitor/antagonistinsightnovelnovel therapeutic interventionnovel therapeuticsoutcome forecastpol Gene Productsresistant strainresponsescreeningsmall moleculesmall molecule librariestherapeutic developmenttherapeutic targettherapy outcome
项目摘要
HTS Targeting HIV-1 Protease Autoprocessing for First in Class Drug Discovery
Project Summary
This proposal is in response to PAR-17-438: Assay development and screening for discovery of chemical probes
or therapeutic agents (R01). The goal of this project is to carry out high-throughput screens and follow-up
characterizations to identify molecules inhibiting HIV-1 protease (PR) autoprocessing with modes of action
(MOAs) different from the currently available protease inhibitors (PIs). In the infected cell, HIV-1 PR is initially
synthesized as part of the Gag-Pol polyprotein precursor with its proteolysis activity tightly suppressed. During
late stage of virion production, the precursor self-catalyzes the cleavage reactions that lead to liberation of the
free mature PR in a temporospatially regulated fashion. The FDA-approved HIV-1 PIs primarily target the
catalytic site of the mature PR and they are significantly less effective at suppressing precursor-mediated
autoprocessing, suggesting that these two forms of HIV-1 PR are enzymatically different. Also, the emergence
of PI resistant strain in patients treated with PI-containing combination antiretroviral therapy (cART) is an ongoing
problem that diminishes treatment efficacy, which warrants the need for new therapeutics. This project seeks to
find novel autoprocessing inhibitors targeting the precursor at regions not recognized by the currently available
PIs. Towards this goal, we have established a cell-based functional assay that has faithfully recapitulated the
autoprocessing phenotypes observed with proviral constructs. This assay has also, for the first time, made it
possible to screen for autoprocessing inhibitors by HTS using AlphaLISA (amplified luminescent proximity
homogeneous assay ELISA) technology. Our pilot screens of ~26K small molecule compounds displayed
satisfactory performance with Z’ factors >0.45, S/N ratios >10, and hit rates <0.1% although no confirmed hit
was identified. Therefore, we plan to screen a collection of natural product extracts (40K extracts, 5-25
compounds per extract, totaling ~0.6 million chemicals) with a wild type and two PI resistant precursors in
collaboration with Dr. David Sherman at University of Michigan Life Sciences Institute (Aim 1). In parallel, we
will team up with Drs. Thomas Chung and Ian Pass at Sanford Burnham Prebys Medical Discovery Institute to
screen their ~350K small molecule library (Aim 2). These HTS campaigns will hopefully identify a handful
confirmed compounds that will be subjected to a battery of established secondary and tertiary assays (Aim 3) in
order to find novel autoprocessing inhibitors that are different from the current HIV-1 PIs in their MOA. This next
generation of therapeutic probes, when used in combination with the current PIs, will implement a new
therapeutic approach: targeting a vital enzyme (HIV-1 protease) at two distinct functional states (precursor and
mature PR) and at different regions (non-catalytic and catalytic sites) at the same time. Such a strategy is
expected to drastically increase difficulty (genetic barrier) for HIV-1 to evolve viable strains simultaneously
resistant to inhibitors from both classes to resist the resistance.
HTS靶向HIV-1蛋白酶自动加工,用于同类新药的发现
项目成果
期刊论文数量(0)
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{{ truncateString('CHAOPING CHEN', 18)}}的其他基金
Assay Development and Validation for Precision Antiretroviral Therapy to Combat Drug Resistance
对抗耐药性的精准抗逆转录病毒疗法的测定开发和验证
- 批准号:
10882256 - 财政年份:2023
- 资助金额:
$ 80.4万 - 项目类别:
HTS Targeting HIV-1 Protease Autoprocessing for First in Class Drug Discovery
HTS 靶向 HIV-1 蛋白酶自动处理以实现一流药物发现
- 批准号:
10553592 - 财政年份:2020
- 资助金额:
$ 80.4万 - 项目类别:
HTS Targeting HIV-1 Protease Autoprocessing for First in Class Drug Discovery
HTS 靶向 HIV-1 蛋白酶自动处理以实现一流药物发现
- 批准号:
10318957 - 财政年份:2020
- 资助金额:
$ 80.4万 - 项目类别:
HTS Targeting HIV-1 Protease Autoprocessing for First in Class Drug Discovery
HTS 靶向 HIV-1 蛋白酶自动处理以实现一流药物发现
- 批准号:
10077828 - 财政年份:2020
- 资助金额:
$ 80.4万 - 项目类别:
Assay Development for Identification of HIV-1 Protease Autoprocessing Specific Inhibitors
HIV-1 蛋白酶自动加工特异性抑制剂鉴定的检测方法开发
- 批准号:
9332334 - 财政年份:2016
- 资助金额:
$ 80.4万 - 项目类别:
Assay Optimization for Identification of Novel HIV-1 Protease Autoprocessing Inhi
新型 HIV-1 蛋白酶自动加工酶鉴定的测定优化
- 批准号:
8789526 - 财政年份:2014
- 资助金额:
$ 80.4万 - 项目类别:
Assay Optimization for Identification of Novel HIV-1 Protease Autoprocessing Inhi
新型 HIV-1 蛋白酶自动加工酶鉴定的测定优化
- 批准号:
8892994 - 财政年份:2014
- 资助金额:
$ 80.4万 - 项目类别:
Isolation and Characterization of Aptamers Targeted to Inhibit HIV Protease Matur
抑制 HIV 蛋白酶成熟的适体的分离和表征
- 批准号:
7756254 - 财政年份:2009
- 资助金额:
$ 80.4万 - 项目类别:
Isolation and Characterization of Aptamers Targeted to Inhibit HIV Protease Matur
抑制 HIV 蛋白酶成熟的适体的分离和表征
- 批准号:
7860304 - 财政年份:2009
- 资助金额:
$ 80.4万 - 项目类别:
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