Developing Cyclopeptide Nef Inhibitors to Facilitate HIV-1 Eradication
开发环肽 Nef 抑制剂以促进 HIV-1 根除
基本信息
- 批准号:10652729
- 负责人:
- 金额:$ 53.86万
- 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:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAdaptor Signaling ProteinAdoptedAffinityAmino AcidsAnimal Disease ModelsAnti-Retroviral AgentsAntigen PresentationBindingBiochemicalBiological AssayBiological AvailabilityBiological ModelsBiophysicsCD4 Positive T LymphocytesCell membraneCell physiologyCell surfaceCellsCellular biologyClathrinClathrin AdaptorsComplexCrystallizationCyclic PeptidesCyclizationCytotoxic T-LymphocytesDataDefense MechanismsDetectionDevelopmentDiseaseDoctor of PhilosophyDown-RegulationEpitopesGoalsHIV-1Host Defense MechanismImmuneImmunologic ReceptorsIn VitroInfectionKnowledgeLaboratoriesLeadMajor Histocompatibility ComplexMediatingModalityMolecular ConformationPatientsPeptidesPermeabilityPhage DisplayPharmaceutical PreparationsPlayPosturePropertyProteinsResolutionRoleSeriesSiteStructureSurfaceT-LymphocyteTailTestingTherapeuticToxic effectTranscription Factor AP-1ViralViral PathogenesisViral PhysiologyVirusVirus ReplicationWorkanalogantibody-dependent cell cytotoxicitybasedesigndrug discoveryenhancer-binding protein AP-2env Gene Productsexperiencehigh throughput screeningimprovedin vivoinhibitorinsightmimeticsnef Genesnef Proteinnovelprotein aminoacid sequenceprotein functionprotein protein interactionrational designrecruitscreeningsmall moleculesmall molecule librariessuccess
项目摘要
PROJECT SUMMARY:
While currently available antiretrovirals block viral replication and thus control HIV-1 infection, they do not cure
the disease; latent reservoirs of replication-competent virus persist. To eradicate HIV-1 infection, novel an-
tiretrovirals must be developed. These drugs would ideally induce the killing of infected cells once latency is
reversed. An attractive direction in developing such antiretrovirals is the inhibition of the HIV-1 Nef protein. By
modulating surface-levels of immune receptors, Nef enables infected cells to evade host defense mechanisms.
Among the many functions of Nef, surface downregulations of CD4 and major histocompatibility complex class
I (MHC-I) are the most prominent and presumably most relevant in antiretroviral drug discovery. By downregu-
lating CD4 from the cell surface, Nef enables CD4-induced epitopes of the viral Env protein to remain con-
cealed, which renders infected cells less sensitive to antibody-dependent cellular cytotoxicity (ADCC). By
downregulating MHC-I, Nef disrupts host antigen presentation so that infected cells are protected from killing
by cytotoxic T lymphocytes (CTLs). Conceivably, therapeutic inhibition of these Nef functions may restore the
activities of ADCC and CTLs, thus facilitating the detection and clearance of infected cells. Crystal structures
solved by us showed that Nef-mediated downregulations of CD4 and MHC-I involve a common site on Nef. In
each case, however, this site is remodeled by Nef’s association with target-specific, hijacked clathrin adaptor
proteins (APs) to uniquely accommodate the intended substrate. Furthermore, when bound to Nef, both the
CD4 cytosolic tail and the MHC-I cytosolic tail adopt curved, near-circular postures, which suggests that this
multifunctional site of Nef is structurally poised to bind curved peptide sequences. We therefore hypothesize
that cyclic peptides mimicking these cytosolic tails may function efficiently as inhibitors to block the correspond-
ing cellular activities of Nef. Cyclic peptides (or cyclopeptides) are a promising, novel class of therapeutics,
which are uniquely capable of disrupting protein-protein interactions. Importantly, high-affinity cyclopeptide in-
hibitors can be developed efficiently using recently established strategies. In this project, we will develop such
cyclopeptide-based Nef inhibitors. Our specific aims are: 1) use our established MOrPH-PhD platform to
screen and select CD4-mimetic cyclopeptide inhibitors that bind to the Nef/AP2 complex in high affinity, and
solve high-resolution crystal structures of the cyclopeptide-bound Nef/AP2 complexes to enable structure-
based derivatization of the inhibitors; 2) use the same work flow to develop and optimize MHC-I-mimetic cyclo-
peptides into potent inhibitors, which block recruitment of MHC-I into the Nef/AP1 complex; 3) use cell-based
assays to characterize the identified Nef inhibitors for their efficacy, cell permeability, and cellular toxicity, and
then use the knowledge learned to guide further derivatizations for improved properties. Successful completion
of this work should yield cyclic peptide-based Nef inhibitors with high affinity in vitro and significant efficacy in
cells, which could ideally be developed into novel antiretrovirals with unique therapeutic potentials.
项目摘要:
虽然目前可用的抗逆转录病毒阻止病毒复制,从而控制HIV-1感染,但它们无法治愈
疾病;具有复制能力的病毒的潜在储藏剂持续存在。为了放射性HIV-1感染,新型
必须开发tiretrovirals。一旦潜伏期为
逆转。开发此类抗逆转录病毒的一个有吸引力的方向是抑制HIV-1 NEF蛋白。经过
NEF调节免疫受体的表面水平使感染细胞能够逃避宿主防御机制。
在NEF的许多功能中,CD4和主要组织相容性复合物的表面下调
I(MHC-I)是抗逆转录病毒药物发现中最突出和最相关的。通过下降 -
NEF从细胞表面进行识别CD4,使CD4诱导的病毒Env蛋白的表位保持不变
Cealed,这使感染细胞对抗体依赖性细胞毒性(ADCC)敏感。经过
下调MHC-I,NEF破坏宿主抗原表现,以保护感染的细胞免于杀死
通过细胞毒性T淋巴细胞(CTL)。可以想象,这些NEF功能的治疗抑制可能会恢复
ADCC和CTL的活性,从而支持被感染细胞的检测和清除。晶体结构
我们解决的表明,NEF介导的CD4和MHC-I的下调涉及NEF上的一个共同位点。在
但是,每种情况下,NEF与特定于目标的,被劫持的网格蛋白适配器的关联都重塑了此站点
蛋白质(AP)独特地适合预期的底物。此外,当绑定到nef时
CD4胞质尾巴和MHC-I胞质尾巴采用弯曲的近圆形位置,这表明这一点
NEF的多功能位点在结构上有毒以结合弯曲的肽序列。因此,我们假设
模仿这些胞质尾巴的循环刺痛可能会有效起作用,因为抑制剂阻止了相应的 -
NEF的细胞活性。环状胡椒(或环肽)是一种有前途的新型治疗,
它具有唯一能够破坏蛋白质蛋白质相互作用的能力。重要的是,高亲和力环皮肽内
可以使用最近建立的策略有效地开发招聘机。在这个项目中,我们将开发这样的
基于环肽的NEF抑制剂。我们的具体目的是:1)使用我们既定的形态平台
屏幕并选择与高亲和力中与NEF/AP2复合物结合的CD4模拟环肽抑制剂,并且
解决环肽结合的NEF/AP2配合物的高分辨率晶体结构,以实现结构 -
基于抑制剂的衍生化; 2)使用相同的工作流来开发和优化MHC-1模拟环境
肽成有效抑制剂,将MHC-I募集到NEF/AP1复合物中; 3)使用基于单元格的
测定确定的NEF抑制剂的效率,细胞渗透性和细胞毒性的测定法和
然后使用学到的知识来指导进一步的衍生化以改善特性。成功完成
这项工作应产生具有高亲和力的基于环状肽的NEF抑制剂,并在体外且效率显着
理想情况下,可以发展为具有独特治疗势的新型抗逆转录病毒。
项目成果
期刊论文数量(0)
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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Rudi Fasan其他文献
Rudi Fasan的其他文献
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{{ truncateString('Rudi Fasan', 18)}}的其他基金
Developing Cyclopeptide Nef Inhibitors to Facilitate HIV-1 Eradication
开发环肽 Nef 抑制剂以促进 HIV-1 根除
- 批准号:
10759561 - 财政年份:2023
- 资助金额:
$ 53.86万 - 项目类别:
Macrocyclic Peptide Modulators of Protein Function
蛋白质功能的大环肽调节剂
- 批准号:
10000964 - 财政年份:2019
- 资助金额:
$ 53.86万 - 项目类别:
Macrocyclic Peptide Modulators of Protein Function
蛋白质功能的大环肽调节剂
- 批准号:
10470247 - 财政年份:2019
- 资助金额:
$ 53.86万 - 项目类别:
Macrocyclic inhibitors of upstream protein activators of the Hedgehog pathway
Hedgehog 通路上游蛋白激活剂的大环抑制剂
- 批准号:
8895869 - 财政年份:2014
- 资助金额:
$ 53.86万 - 项目类别:
Macrocyclic inhibitors of upstream protein activators of the Hedgehog pathway
Hedgehog 通路上游蛋白激活剂的大环抑制剂
- 批准号:
8755152 - 财政年份:2014
- 资助金额:
$ 53.86万 - 项目类别:
Selective P450 Oxidation Catalysts for Synthesis of Bioactive Molecules
用于合成生物活性分子的选择性 P450 氧化催化剂
- 批准号:
8472499 - 财政年份:2012
- 资助金额:
$ 53.86万 - 项目类别:
Metalloprotein catalysts for asymmetric synthesis
用于不对称合成的金属蛋白催化剂
- 批准号:
10210696 - 财政年份:2012
- 资助金额:
$ 53.86万 - 项目类别:
Metalloprotein Catalysts for Asymmetric Synthesis
用于不对称合成的金属蛋白催化剂
- 批准号:
9896830 - 财政年份:2012
- 资助金额:
$ 53.86万 - 项目类别:
Selective P450 Oxidation Catalysts for Synthesis of Bioactive Molecules
用于合成生物活性分子的选择性 P450 氧化催化剂
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9272479 - 财政年份:2012
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购置超临界流体色谱系统
- 批准号:
10797957 - 财政年份:2012
- 资助金额:
$ 53.86万 - 项目类别:
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