HIV-1 Maturation

HIV-1成熟

基本信息

  • 批准号:
    10262147
  • 负责人:
  • 金额:
    $ 69.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

While currently available antiretroviral therapies are highly effective in suppressing HIV-1 replication in treated patients, these drugs are not curative. Patients are thus required to remain on continuous, lifelong therapy, which has been associated with a variety of toxicities and adverse effects. Also, over time, viral resistance is likely to pose an increasingly serious problem for patients on therapy. The development of novel classes of inhibitors that block steps in the replication cycle distinct from those targeted by currently available drugs is therefore a high priority. We have played a leading role in the development of one such novel class of HIV-1 antiviral drugs, the maturation inhibitors (MIs)._____In the HIV-1 replication cycle, Gag proteins are synthesized as a polyprotein precursor (Pr55Gag) that is cleaved by the viral protease (PR) during virus release from the infected cell. Completion of the Gag processing cascade is essential for virus maturation and infectivity. In collaboration with Panacos Pharmaceuticals, we found that 3-0-(3'-3'-dimethylsuccinyl) betulinic acid (PA-457, now known primarily as bevirimat or BVM) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag-processing pathway, the conversion of the capsid-spacer peptide 1 (CA-SP1) region of HIV-1 Gag to mature CA. Clinical trials conducted with BVM produced mixed results; in some patients, significant reductions in viral loads were achieved, whereas in other patients, no benefit of BVM therapy was observed. We and others demonstrated that this lack of response was linked to polymorphisms in SP1. We have also studied in detail the target, mechanism of action, and resistance pathways of a second, structurally distinct MI discovered by Pfizer (PF-46396 or PF96). We found that resistance to PF96 was conferred by mutations not only in the vicinity of the CA-SP1 cleavage site [where resistance to BVM maps] but also upstream in the CA major homology region (MHR). Notably, the MHR mutants that arose during selection for PF96 resistance were markedly PF96 dependent. The MHR mutants, which on their own are highly deficient in assembly and replication, could also revert by acquiring a second-site mutation in SP1 residue 8 (T8I). The study of the PF96-dependent MHR mutants and the T8I compensatory mutant is providing a wealth of information about the role of CA and SP1 in assembly and maturation and will advance our understanding of the structural properties of SP1. Our research on BVM and PF96 has provided novel insights into the structure-function relationship between CA and SP1, as well as a framework for increased structural understanding of HIV-1 MI activity._____We have now forged a multidisciplinary collaborative effort, together with chemists in Dr. Joel Schneider's lab (NCI), at DFH Pharmaceuticals, and at the Hetero Research Foundation (HRF), to develop "second-generation" BVM analogs that are significantly more potent and broadly active against polymorphic isolates of HIV-1 than BVM or PF96. The best of these analogs are undergoing preclinical testing in anticipation of clinical trials. More long term, we hypothesize that defining the structure of the MI-binding pocket in HIV-1 Gag will greatly facilitate the development of novel and more potent inhibitors; to this end, we are collaborating with several structural biology labs to define the structure of the CA-SP1 region in the immature Gag lattice, in both the presence and the absence of bound inhibitor. Our working hypothesis is that MIs block CA-SP1 processing by stabilizing a six-helix bundle that extends from the C-terminus of CA into SP1. Resistance mutations confer escape by stabilizing this helical bundle. We are collaborating with structural biologists to define the structure of MI-bound Gag by NMR techniques. We are also studying the effect of inositol hexakisphosphate (IP6) on MI activity. We believe that our work in this project will be transformative both in understanding the structure and function of the CA-SP1 region of Gag, which plays critical roles in HIV-1 assembly and maturation, and in developing MIs as a novel class of antiretroviral agents.
虽然目前可用的抗逆转录病毒疗法在抑制接受治疗的患者中的HIV-1复制方面非常有效,但这些药物不能治愈。因此,患者需要持续终身治疗,这与各种毒性和不良反应有关。此外,随着时间的推移,病毒耐药性可能会给接受治疗的患者带来越来越严重的问题。因此,开发新型抑制剂是一个高度优先事项,这些抑制剂可以阻断复制周期中的步骤,而不是目前可用的药物所针对的步骤。我们在开发一种新的HIV-1抗病毒药物成熟抑制剂(MIs)方面发挥了主导作用。在HIV-1复制周期中,Gag蛋白合成为多蛋白前体(Pr 55 Gag),在病毒从感染细胞释放期间被病毒蛋白酶(PR)切割。Gag加工级联的完成对于病毒成熟和感染性是必不可少的。在与Panacos Pharmaceuticals的合作中,我们发现3-0-(3 '-3'-二甲基琥珀酰基)桦木酸(PA-457,现在主要称为bevirimat或BVM)通过特异性阻断Gag加工途径中的后期步骤,即HIV-1 Gag的capture-spacer peptide 1(CA-SP1)区域向成熟CA的转化,有效抑制HIV-1成熟。使用BVM进行的临床试验产生了混合结果;在一些患者中,病毒载量显著降低,而在其他患者中,未观察到BVM治疗的益处。我们和其他人证明了这种反应的缺乏与SP1的多态性有关。我们还详细研究了辉瑞发现的第二种结构不同的MI(PF-46396或PF 96)的靶点、作用机制和耐药途径。我们发现,对PF 96的耐药性不仅是由CA-SP1切割位点附近的突变(对BVM的耐药性图谱)赋予的,而且也是由CA主要同源区(MHR)上游的突变赋予的。值得注意的是,在选择PF 96抗性期间产生的MHR突变体是显著的PF 96依赖性的。MHR突变体本身在组装和复制方面存在高度缺陷,也可以通过在SP1残基8(T8 I)中获得第二个位点突变而恢复。PF 96依赖性MHR突变体和T8 I补偿突变体的研究提供了丰富的信息CA和SP1在组装和成熟中的作用,并将推进我们对SP1结构特性的理解。我们对BVM和PF 96的研究为CA和SP1之间的结构-功能关系提供了新的见解,并为增加对HIV-1 MI活性的结构理解提供了框架。我们现在已经与Joel Schneider博士实验室(NCI),DFH制药公司和HRF研究基金会(HRF)的化学家一起建立了一个多学科的合作努力,以开发“第二代”BVM类似物,这些类似物对HIV-1的多态性分离株比BVM或PF 96更有效和更广泛。这些类似物中最好的正在进行临床前测试,以期待临床试验。从更长远的角度来看,我们假设定义HIV-1 Gag中MI结合口袋的结构将极大地促进新型和更有效抑制剂的开发;为此,我们正在与几个结构生物学实验室合作,在存在和不存在结合抑制剂的情况下,定义未成熟Gag晶格中CA-SP1区域的结构。我们的工作假设是,MI阻止CA-SP1的加工稳定的六螺旋束,从C-末端CA延伸到SP1。抗性突变通过稳定这个螺旋束来赋予逃逸。我们正在与结构生物学家合作,通过NMR技术确定MI结合的Gag的结构。我们还研究了肌醇六磷酸(IP 6)对MI活性的影响。我们相信,我们在这个项目中的工作将是变革性的,无论是在理解CA-SP1区域的结构和功能的Gag,这在HIV-1的组装和成熟中发挥着关键作用,并在开发MI作为一种新型的抗逆转录病毒药物。

项目成果

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{{ truncateString('eric freed', 18)}}的其他基金

Antagonism of Coronavirus Spike Proteins by Cellular Host Factors
细胞宿主因子对冠状病毒刺突蛋白的拮抗作用
  • 批准号:
    10487091
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Inhibition of HIV-1 Maturation
HIV-1 成熟的抑制
  • 批准号:
    8763211
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Inhibition of HIV-1 Maturation
HIV-1 成熟的抑制
  • 批准号:
    8552819
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Gag Trafficking, Assembly, and Release
堵嘴贩运、组装和释放
  • 批准号:
    10702636
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Retroviral Gag Trafficking, Env Incorporation, and Virus Assembly
逆转录病毒堵嘴贩运、Env 合并和病毒组装
  • 批准号:
    8349150
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Inhibition of HIV-1 Maturation
HIV-1 成熟的抑制
  • 批准号:
    8349153
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Retrovirus Budding and Endosomal Sorting
逆转录病毒出芽和内体分选
  • 批准号:
    8552818
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Retroviral Gag Trafficking, Env Incorporation, and Virus Assembly
逆转录病毒堵嘴贩运、Env 合并和病毒组装
  • 批准号:
    7733213
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
Inhibition of HIV-1 Maturation
HIV-1 成熟的抑制
  • 批准号:
    7592927
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
HIV-1 Maturation
HIV-1成熟
  • 批准号:
    9343696
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:

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RESISTANCE OF HIV-1 TO ANTI-RETROVIRAL AGENTS
HIV-1 对抗逆转录病毒药物的耐药性
  • 批准号:
    3030975
  • 财政年份:
    1993
  • 资助金额:
    $ 69.71万
  • 项目类别:
POLYMERICS DELIVERY SYSTEMS FOR ANTI-RETROVIRAL AGENTS
抗逆转录病毒药物的聚合物递送系统
  • 批准号:
    3489187
  • 财政年份:
    1990
  • 资助金额:
    $ 69.71万
  • 项目类别:
DEVELOPMENTAL VIROLOGY RESEARCH--RESISTANCE TO ANTI-RETROVIRAL AGENTS
发育病毒学研究——抗逆转录病毒药物的耐药性
  • 批准号:
    2335293
  • 财政年份:
  • 资助金额:
    $ 69.71万
  • 项目类别:
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