PROTACS Against Nef as a Functional Cure for HIV Infection
PROTACS 针对 Nef 作为 HIV 感染的功能性治疗
基本信息
- 批准号:10200007
- 负责人:
- 金额:$ 29.78万
- 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:2020-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAcquired Immunodeficiency SyndromeActive SitesAffinityAnti-Retroviral AgentsAntigen PresentationAutologousBindingBinding ProteinsBiological AssayBiological AvailabilityCD4 Positive T LymphocytesCaco-2 CellsCell surfaceCellsCellular AssayChemicalsChimera organismClinical ResearchCoupledCytotoxic T-LymphocytesDataDevelopmentDown-RegulationDrug IndustryDrug KineticsDrug TargetingFoundationsFoxesFutureGoalsHIVHIV InfectionsHIV-1Half-LifeHumanIceImmuneImmune systemIn VitroIndividualLaboratoriesLibrariesLifeLife Cycle StagesLigand BindingLigandsLiteratureLiver MicrosomesMediatingMetabolicMidazolamMolecular WeightMusOralPatientsPeripheral Blood Mononuclear CellPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPhasePlasma ProteinsPolyubiquitinationPositioning AttributeProgram DevelopmentPropertyProteinsRecombinantsRelapseReportingResearchResponse LatenciesRoleSeriesSmall Business Technology Transfer ResearchSolubilityStructureSurface Plasmon ResonanceSystemTestingTherapeuticToxicologyUniversitiesViralViral reservoirVirulence FactorsWorkantiretroviral therapyaqueousbasecell typeclinical translationcytotoxicitydrug candidatedrug developmentefficacy evaluationflexibilityhumanized mousein vivoin vivo evaluationinhibitor/antagonistinnovationinsightlatent HIV reservoirmouse modelnef Proteinnovelnovel strategiesnovel therapeutic interventionphase 1 studypre-clinicalpreventresponsesmall moleculetherapeutic targetubiquitin-protein ligase
项目摘要
Abstract. Existing antiretroviral drugs do not clear HIV-1 latent reservoirs, underscoring the urgent need for
new therapeutic strategies. The HIV-1 Nef accessory factor is an attractive target for drug development because
of its critical roles in the HIV-1 life cycle and immune system escape. Our group has discovered novel small
molecules that bind directly to Nef and block many of its functions, including enhancement of viral infectivity and
replication in donor PBMCs. Importantly, our Nef inhibitors rescue cell-surface MHC-I expression in latently in-
fected, patient-derived CD4 T-cells, enabling recognition and killing by autologous CTLs. Thus, Nef inhibitors
represent an innovative approach to antiretroviral therapy that may provide a path to eradication of viral reser-
voirs. Our most promising class of inhibitors (hydroxypyrazoles) bind tightly to their Nef protein target in vitro
with KD values in the nM to pM range. However, Nef lacks an active site, which has complicated traditional
medicinal chemistry optimization of existing compounds for in vivo testing due to the lack of correlation between
Nef binding affinity in vitro and antiretroviral activity in cell-based systems.
To circumvent this issue, we propose to use our existing Nef-binding compounds to develop Proteolytic
Targeting Chimera (PROTAC) molecules for the targeted destruction of the Nef protein in HIV-infected cells. In
this approach, existing hydroxypyrazole Nef-binding compounds will be coupled to ligands for ubiquitin E3 lig-
ases via a flexible linker. The resulting Nef PROTACs are anticipated to catalyze the proteolytic degradation of
Nef via E3-mediated polyubiquitination and proteasomal targeting. A major advantage of the PROTAC approach
is that it requires only a selective binder of the target protein (Nef in this case) and not a functional inhibitor. We
anticipate that selective PROTAC-mediated degradation will eliminate all Nef functions, including rescue of cell
surface MHC-I mediated HIV-1 antigen presentation, leading to clearance of HIV+ cells via the CTL response as
part of a strategy for latent reservoir reduction and functional cure. More generally, the PROTAC approach has
generated a great deal of excitement in the pharmaceutical industry, because it provides new avenues to inhibit
proteins previously considered undruggable. While PROTACs have higher molecular weights that typical small
molecule drugs, recent preclinical and Phase I clinical studies have demonstrated activity in vivo as well as oral
bioavailability. For this Phase I STTR project, HIV-1 Nef PROTAC development will combine the pharmaceutical
and medicinal chemistry expertise of the Fox Chase Chemical Diversity Center, Inc. (www.fc-cdci.com; FCCDC)
with the expertise of the Smithgall Lab at the University of Pittsburgh in HIV-1 Nef structure, function and inhibitor
analysis. Our broad goal is to synthesize and test a series of Nef PROTACs with different Nef-targeting moieties,
linkers, and E3 ubiquitin ligase ligands to identify compounds suitable for in vivo proof-of-concept studies. Suc-
cessful completion of Phase I will provide a strong foundation for an expanded drug development program in
Phase II, with the ultimate goal of clinical translation.
摘要。现有的抗逆转录病毒药物不能清除HIV-1潜伏库,因此迫切需要
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Thomas E. Smithgall其他文献
ID: 36: MCPIP1/Regnase-1 is a negative feedback inhibitor regulating IL-17 signaling and inflammation
- DOI:
10.1016/j.cyto.2015.08.066 - 发表时间:
2015-11-01 - 期刊:
- 影响因子:
- 作者:
Abhishek Garg;Nilesh Amatya;Kong Chen;J. Agustin Cruz;Prerna Grover;Natasha Whibley;Heather R. Conti;Gerard Hernandez Mir;Tatiana Sirakova;Erin C. Childs;Thomas E. Smithgall;Partha S. Biswas;Jay K. Kolls;Mandy J. McGeachy;Pappachan E. Kolattukudy;Sarah L. Gaffen - 通讯作者:
Sarah L. Gaffen
Allosteric restriction enhances sensitivity of the AML-associated Src-family kinase Fgr to ATP-site inhibitors
- DOI:
10.1016/j.bpj.2023.11.2076 - 发表时间:
2024-02-08 - 期刊:
- 影响因子:
- 作者:
Giancarlo Gonzalez-Areizaga;John J. Alvarado;Du Shoucheng;Thomas E. Smithgall - 通讯作者:
Thomas E. Smithgall
Mutagenesis of the HIV-1 Nef homodimerization interface suppresses multiple functions without altering the core fold
- DOI:
10.1016/j.bpj.2023.11.1237 - 发表时间:
2024-02-08 - 期刊:
- 影响因子:
- 作者:
Catherine E. Thomas;Frank Heinrich;John J. Alvarado;Thomas E. Smithgall - 通讯作者:
Thomas E. Smithgall
Membrane Bound Structure of the HIV-1 Accessory Protein Nef
- DOI:
10.1016/j.bpj.2017.11.226 - 发表时间:
2018-02-02 - 期刊:
- 影响因子:
- 作者:
Rebecca Eells;Kindra Whitlatch;Bradley Treece;Frank Heinrich;John Jeff Alvarado;Thomas E. Smithgall;Mathias Lösche - 通讯作者:
Mathias Lösche
Membrane Binding of HIV-1 Accessory Protein Nef on Sparsely-Tethered Bilayer Lipid Membranes: An Spr Study
- DOI:
10.1016/j.bpj.2018.11.350 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Christopher Kervick;Manish Aryal;Frank Heinrich;Thomas E. Smithgall;Mathias Lösche - 通讯作者:
Mathias Lösche
Thomas E. Smithgall的其他文献
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{{ truncateString('Thomas E. Smithgall', 18)}}的其他基金
Precision Targeting of Myeloid Src-family Kinases in Acute Myelogenous Leukemia
急性髓系白血病中髓系 Src 家族激酶的精确靶向
- 批准号:
10308327 - 财政年份:2021
- 资助金额:
$ 29.78万 - 项目类别:
PROTACS Against Nef as a Functional Cure for HIV Infection
PROTACS 针对 Nef 作为 HIV 感染的功能性治疗
- 批准号:
10079715 - 财政年份:2020
- 资助金额:
$ 29.78万 - 项目类别:
Precision Targeting of Myeloid Src-family Kinases in Acute Myelogenous Leukemia
急性髓系白血病中髓系 Src 家族激酶的精确靶向
- 批准号:
10687861 - 财政年份:2019
- 资助金额:
$ 29.78万 - 项目类别:
Precision Targeting of Myeloid Src-family Kinases in Acute Myelogenous Leukemia
急性髓系白血病中髓系 Src 家族激酶的精确靶向
- 批准号:
10388497 - 财政年份:2019
- 资助金额:
$ 29.78万 - 项目类别:
Precision Targeting of Myeloid Src-family Kinases in Acute Myelogenous Leukemia
急性髓系白血病中髓系 Src 家族激酶的精确靶向
- 批准号:
9814793 - 财政年份:2019
- 资助金额:
$ 29.78万 - 项目类别:
Precision Targeting of Myeloid Src-family Kinases in Acute Myelogenous Leukemia
急性髓系白血病中髓系 Src 家族激酶的精确靶向
- 批准号:
10740923 - 财政年份:2019
- 资助金额:
$ 29.78万 - 项目类别:
Precision Targeting of Myeloid Src-family Kinases in Acute Myelogenous Leukemia
急性髓系白血病中髓系 Src 家族激酶的精确靶向
- 批准号:
10524124 - 财政年份:2019
- 资助金额:
$ 29.78万 - 项目类别:
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