权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

METALLOPEPTIDES OF GP41 IN HIV-1 FUSION INHIBITION

GP41 的金属肽抑制 HIV-1 融合

基本信息

批准号：
7168919
负责人：
MIRIAM GOCHIN
金额：
$ 9.35万
依托单位：
TOURO UNIVERSITY OF CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-02 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7168919
关键词：
HIV envelope protein gp41 antiAIDS agent antiviral agents binding sites combinatorial chemistry conformation drug design /synthesis /production fluorescent dye /probe molecular probes peptide analog protein binding protein structure function

项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on the development of entry inhibitors against Human Immunodeficiency Virus Type-1, by targeting the viral fusion protein gp41. Gp41 mediates fusion to mammalian host cells via a highly conserved coiled coil domain. The hypothesis is that compounds that bind to this domain will act as fusion inhibitors by preventing the gp41 conformational rearrangement required for fusion. Discovery of inhibitors to the gp41 coiled coil is hampered by the fact that this domain is not readily accessible in solution, being buried in intact gp41 and unstable when excised from the rest of the protein. We have developed a stabilized coiled coil construct through the use of bidentate bipyridyl groups covalently attached at the N-termini of gp41 peptides. The addition of transition metal ion to the bipyridylated peptides stabilizes the trimeric helical structure of the coiled coil, through the formation of an octahedral tris-bipyridyl complex, and removes non-specific aggregation of the hydrophobic peptide. The goal of this proposal is to make use of the probe properties of various metal ions to establish a screening and structural assay for inhibitors which bind to the coiled coil. 1) Discrete metal ion - coordinated constructs which represent the gp41 inner coiled coil will be developed and analyzed by NMR structure determination. 2) Constructs will be used in the development and refinement of a fluorescence binding assay to detect compound binding to the coiled coil. 3) Library screening will be conducted and successful hits analyzed with in vitro syncytium and viral infectivity assays. The metal ion used in each of these specific aims will be selected to have diamagnetic, paramagnetic or fluorescent properties, as needed, to be utilized in the biophysical assays. The long term goal of this proposal is to develop promising non-peptide drug candidates for HIV-1 fusion inhibition.

描述（由申请人提供）：该提案的重点是通过靶向病毒融合蛋白gp 41开发针对人类免疫缺陷病毒1型的进入抑制剂。Gp 41通过高度保守的卷曲螺旋结构域介导与哺乳动物宿主细胞的融合。假设是，结合到该结构域的化合物将通过阻止融合所需的gp 41构象重排而充当融合抑制剂。gp 41卷曲螺旋抑制剂的发现受到以下事实的阻碍：该结构域在溶液中不易接近，被埋在完整的gp 41中，并且当从蛋白质的其余部分切除时不稳定。我们已经开发了一种稳定的卷曲螺旋结构，通过使用共价连接在gp 41肽的N-末端的双齿联吡啶基团。向联吡啶化肽中加入过渡金属离子通过形成八面体三联吡啶络合物稳定了卷曲螺旋的三聚体螺旋结构，并消除了疏水肽的非特异性聚集。本提案的目的是利用各种金属离子的探针性质来建立与卷曲螺旋结合的抑制剂的筛选和结构测定。1)将开发代表gp 41内部卷曲螺旋的离散金属离子配位构建体，并通过NMR结构测定进行分析。2)构建体将用于荧光结合试验的开发和改进，以检测化合物与卷曲螺旋的结合。3)将进行文库筛选，并使用体外合胞体和病毒感染性试验分析成功命中。在这些特定目的中的每一个中使用的金属离子将根据需要被选择为具有抗磁性、顺磁性或荧光性质，以用于生物物理测定。该提案的长期目标是开发有希望的用于HIV-1融合抑制的非肽候选药物。