HIGH RES STRUCT OF HUMAN VIRUSES & VIRAL PROTEINS: SYNCH RADIATION AT CHESS: HIV

人类病毒的高分辨率结构

• 批准号: 7955535
• 负责人: EDWARD ARNOLD
• 金额: $ 3.4万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955535
• 关键词: Acquired Immunodeficiency Syndrome; Antiviral Agents; Belgium; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Development; Dose; Drug Design; Drug resistance; Foundations; Funding; Grant; HIV; HIV Envelope Protein gp120; HIV-1; Human; Human Virus; Immune response; Institution; Laboratories; Lead; Molecular; Mutation; Paper; Patients; Pharmaceutical Preparations; Phase; Process; Radiation; Regulation; Research; Research Personnel; Resources; Rhinovirus; Screening procedure; Series; Source; Structure; Structure-Activity Relationship; TALL-1 protein; TMC120-R147681; United States National Institutes of Health; V3 Loop; Variant; Viral Load result; Viral Proteins; Virus; analog; base; beamline; clinically relevant; cytokine; design; env Gene Products; inhibitor/antagonist; metabolic abnormality assessment; nucleoside inhibitor; resistance mutation; three dimensional structure; Acquired Immunodeficiency Syndrome; Antiviral Agents; Belgium; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Development; Dose; Drug Design; Drug resistance; Foundations; Funding; Grant; HIV; HIV Envelope Protein gp120; HIV-1; Human; Human Virus; Immune response; Institution; Laboratories; Lead; Molecular; Mutation; Paper; Patients; Pharmaceutical Preparations; Phase; Process; Radiation; Regulation; Research; Research Personnel; Resources; Rhinovirus; Screening procedure; Series; Source; Structure; Structure-Activity Relationship; TALL-1 protein; TMC120-R147681; United States National Institutes of Health; V3 Loop; Variant; Viral Load result; Viral Proteins; Virus; analog; base; beamline; clinically relevant; cytokine; design; env Gene Products; inhibitor/antagonist; metabolic abnormality assessment; nucleoside inhibitor; resistance mutation; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A long-term collaborative structure-based drug design project with Paul Janssen and colleagues at the Center for Molecular Design, Janssen Research Foundation in Belgium, has yielded some very exciting potential drugs for the treatment of AIDS. We have studied the interactions of a series of non-nucleoside inhibitors (NNRTIs) of HIV-1 RT by determining the structures of numerous analogs during the process. The use of MacCHESS has been absolutely essential to the process. Synthesis of hundreds of compounds in multiple structurally related classes of NNRTIs led to the discovery of the dianilinopyrimidine (DAPY) analogs (Ludovici et al., 2001, 3 papers). A combination of antiviral screening against HIV variants containing clinically relevant mutations, metabolic studies, and three-dimensional structure-activity relationships led to the identification of TMC120-R147681 and TMC125-R165335 as highly potent broad-spectrum inhibitors of HIV replication. Initial human studies with these co mpounds have been very encouraging. Twice-daily doses of 100 mg TMC120-R147681 given to patients in Phase I/II human clinical trials led to a mean decrease in viral load of 1.5 log10 (roughly 30-fold) in one week. No drug-resistance mutations in HIV-1 RT were observed to emerge during the trial, which is unprecedented for this type of inhibitor. Throughout the development process, we have determined crystal structures of lead compounds with HIV-1 RT, and these structures have been used to guide understanding of the three-dimensional determinants of inhibitor activity and interactions with drug-resistance mutations. Most of the structures used in this process were determined using radiation from the CHESS F1 beamline. Other results from the laboratory that have been obtained using the resources at MacCHESS include the determination of the structure (Ding et al., in press) of a human rhinovirus:HIV-1 chimeric virus that displays a segment from the HIV-1 V3 loop (also known as the "principal neutralizing domain" of the gp120 envelope protein) and determination of the structure of B-lymphocyte stimulator (BlyS), a human cytokine involved in regulation of immune responses (Oren et al., 2002).

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 比利时的Janssen Research Foundation与Paul Janssen及其同事的长期基于结构的药物设计项目，为艾滋病的治疗提供了一些非常令人兴奋的潜在药物。我们已经研究了HIV-1 RT的一系列非核苷抑制剂（NNRTIS）的相互作用，通过确定过程中众多类似物的结构。 MacChess的使用对于该过程绝对至关重要。在多种结构相关类别的NNRTI类别中的数百种化合物的合成导致发现了Dianilinopyrimidine（Dapy）类似物（Ludovici等，2001，3篇论文）。针对含有临床相关突变，代谢研究和三维结构活性关系的抗病毒筛查的组合，导致鉴定TMC120-R147681和TMC125-R165335是HIV重复的HIV宽光谱抑制剂。这些共同体的最初人类研究非常令人鼓舞。在I/II期人类临床试验中给予患者的两次每日剂量为100 mg TMC120-R147681，导致病毒载量的平均降低在一周内（约30倍）。在试验期间，没有观察到HIV-1 RT中的药物抗性突变，这对于这种类型的抑制剂是前所未有的。在整个开发过程中，我们确定了与HIV-1 RT的铅化合物的晶体结构，这些结构已用于指导对抑制剂活性的三维决定因素的理解以及与药物抗性突变的相互作用。在此过程中使用的大多数结构使用来自国际象棋F1梁线的辐射确定。使用MacChess资源获得的实验室的其他结果包括确定人类鼻病毒病毒的结构（丁等，印刷中）：HIV-1嵌合病毒，该病毒显示了HIV-1 V3回路中的一部分（也称为GP120 Enveloper Protine of The Blys of the Blys of the Blys of HIV-1 v3循环（也称为“也称为中和中和）的结构（也称为B）。与免疫反应调节有关的人类细胞因子（Oren等，2002）。