Investigation of ATV-Based Heterobifunctional Degraders to Combat Growing HIV-1 PR Inhibitor Resistance
研究基于 ATV 的异双功能降解剂以对抗日益增长的 HIV-1 PR 抑制剂耐药性
基本信息
- 批准号:10484347
- 负责人:
- 金额:$ 22.7万
- 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:2022-08-04 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAntiviral AgentsAtazanavirAutoimmune DiseasesBindingBinding ProteinsBinding SitesBiologicalBiological AssayBiological AvailabilityBiologyCell membraneCellsClinicClinical TrialsComplexComputing MethodologiesDevelopmentDimerizationDrug resistanceEpidemicEventExhibitsFailureFoundationsFutureGoalsHIVHIV InfectionsHIV ProteaseHIV Protease InhibitorsHIV resistanceHIV-1HIV-1 proteaseImpairmentInfectionInvestigationLeadLengthLigandsLigaseMediatingMembraneModalityModelingMolecular ConformationMulti-Drug ResistanceMutationNuclearNuclear EnvelopeOrganic SynthesisPatientsPeptide HydrolasesPharmaceutical ChemistryPharmaceutical PreparationsPharmacotherapyPredispositionProbabilityProcessPropertyProtease InhibitorProteinsReagentRegimenResistanceResistance developmentSeriesSiteStructureTestingTherapeuticTherapeutic InterventionUbiquitinationVariantViralVirionWorkanalogantimicrobial drugantiretroviral therapyassay developmentbasecombatdesigndimerdrug developmentdrug discoveryexperiencehigh rewardhigh riskin vitro activityin vivoinhibitorlead optimizationmembrane assemblynext generationnovelnovel strategiesnovel therapeutic interventionparticlepol Gene Productspre-exposure prophylaxispreventprospectiveprototyperecruitrefractory cancerresistant strainscreeningsimulationsmall molecule inhibitortrendubiquitin-protein ligaseviral resistance
项目摘要
PROJECT SUMMARY/ABSTRACT
Heterobifunctional targeted protein degraders (TPDs) offer advantages over traditional occupancy-based
inhibitors including a unique catalytic mechanism of action (MOA), greater target selectivity, and a reduced
probability for resistance development. TPDs are known to effectively target not only cytosolic proteins, but also
nuclear and membrane-bound proteins. This therapeutic modality shows great promise for treating drug-resistant
cancers and autoimmune diseases but has seen only limited application in antiviral drug discovery. HIV-1
protease (PR) is essential for proteolytic cleavage of Gag and Gag-Pol polyproteins and, thus, virion maturation
and infectivity. Gag-Pol forms dynamic dimers at plasma membrane assembly/budding sites, allowing the
embedded precursor PR to dimerize as a prerequisite for auto-processing. We identified precursor PR/Gag-Pol
as a promising target for protease inhibitor (PI)-based TPDs. The widely used HIV-1 PI, Atazanavir (ATV), is
amenable to conjugation with linkers and ubiquitin E3 ligase recruiting ligands to serve as prototype HIV-1 TPDs.
Importantly, ATV inhibits activity of mature PR as well as autoprocessing of precursor PR/Gag-Pol during the
assembly and budding processes. The OBJECTIVE of this study is to show proof-of-concept that HIV-1 Gag-
Pol assembling on the inner leaflet of the plasma membrane can be targeted for aberrant ubiquitination,
degradation, and/or inhibition, thereby impairing HIV infectivity. Importantly, due to TPDs’ established MOA, even
low-affinity Gag-Pol/TPD interactions are likely to lead to impaired Gag-Pol function. Thus, we pose the
HYPOTHESIS that novel ATV-based TPDs will not only augment the inhibition of ATV-sensitive HIV-1 strains
compared to ATV, but also exhibit increased and broader biological activity against drug-resistant variants.
The objective of AIM 1 is to design and synthesize ATV-based TPDs built on state-of-the-art computational
methods and predictive physicochemical properties currently accepted for in vivo active TPDs. Our approach
will feature a modular TPD design to establish the appropriate ATV attachment point, E3 ligase recruiter, and
length and composition of linker required for HIV-1 Gag-Pol ubiquitination/proteasomal degradation. The goal
of AIM 2 is to provide proof-of-concept that ATV-TPDs exert superior activity versus ATV against wild type and
PI-resistant HIV-1 strains. We will systematically screen four series of novel ATV-TPD for activity in vitro, in
single-round infectivity, and in multi-round replication assays to identify the most promising ATV-TPD candidates.
The latter will be tested in complementary limited-scope mechanistic studies, including comparing ATV-TPDs
with analogs bearing inactive E3-ligase ligands, to probe if antiviral activity is consistent with the proposed MOA.
The IMPACT will be TPDs targeting HIV-1 Gag-Pol and precursor PR that limit infectivity and replication through
a mechanism distinct from occupancy-based HIV-1 PI. This will spur the future development of efficacious
regimens against PI-resistant HIV strains with reduced susceptibility for resistance development.
项目摘要/摘要
异质靶向蛋白质降解器(TPD)提供了比传统基于占用的优势
包括独特的催化作用机理(MOA),更大的目标选择性和降低的抑制剂
抵抗发展的可能性。
核和膜结合的蛋白质。
癌症和自身免疫性疾病,但仅在抗病毒药物发现中使用了有限的应用
蛋白酶(PR)对于GAG和POL多蛋白的蛋白质裂解至关重要,因此是病毒体成熟
和感染性。
嵌入的前体PR二聚在自动加工的先决条件下。
作为普罗特抑制剂(PI)的有前途的靶标的TPD。
与连接器和泛素E3连接酶募集配体一起用作HIV-1 TPD的原型。
重要的是,ATV抑制成熟的抑制作用以及在n in n in th in w in th n n n n n n n n n n n n n n n n n n th n th和ofoprocestors抑制
组装和萌芽过程。
在质膜的内部小叶上组装可以针对异常的泛素化,
降解和/或吸收,因此,由于TPDS的MO,也会损害HIV感染力。
低亲和力的GAG-POL/TPD相互作用可能导致GAG-POL功能受损。
假设基于ATV的新型TPD不仅会增加对ATV敏感HIV-1菌株的抑制
与ATV相比,但也表现出对抗药性变体的不良和生物活性。
AIM 1的目的是设计和合成基于ATV的TPD,以最先进的计算为基础
当前接受体内活性TPD的方法和预测性能
将采用模块化TPD设计,以建立适当的ATV附件E3连接酶招聘器和
HIV-1 GAG-POL泛素化/蛋白酶体降解所需的长度和组成。
AIM 2的概念证明ATV-TPD对野生型Ande和ATV发挥优势活动
耐PI HIV-1菌株。
单轮感染性以及多轮复制测定法,以识别最有希望的ATV-TPD候选物。
后者将在互补的有限考验机械研究中进行测试
使用类似物轴承不活跃的E3 - 连接酶配体,以探测抗活性与支撑MOA一致。
影响将是针对HIV-1 GAG-POL和前体PR的TPD,该PR限制了感染和复制
与基于占用的HIV-1 PI不同的机制。
针对耐PI的HIV菌株的方案,耐药性发育的敏感性降低。
项目成果
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CHRISTINA OCHSENBAUER其他文献
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{{ truncateString('CHRISTINA OCHSENBAUER', 18)}}的其他基金
Investigation of ATV-Based Heterobifunctional Degraders to Combat Growing HIV-1 PR Inhibitor Resistance
研究基于 ATV 的异双功能降解剂以对抗日益增长的 HIV-1 PR 抑制剂耐药性
- 批准号:
10676954 - 财政年份:2022
- 资助金额:
$ 22.7万 - 项目类别:
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