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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。比利时杨森研究基金会分子设计中心的Paul Janssen及其同事进行了一项长期合作的基于结构的药物设计项目，已经产生了一些非常令人兴奋的治疗艾滋病的潜在药物。我们研究了一系列非核苷抑制剂（NNRTIs）在HIV-1 RT过程中的相互作用，通过确定许多类似物的结构。在这个过程中，使用MacCHESS是绝对必要的。在合成了数百种结构相关的nnrti类化合物后，发现了diilinopy嘧啶（DAPY）类似物（Ludovici et al., 2001,3篇论文）。结合对含有临床相关突变的HIV变异体的抗病毒筛选、代谢研究和三维结构-活性关系，鉴定出TMC120-R147681和TMC125-R165335是高效的HIV复制广谱抑制剂。对这些化合物的初步人体研究非常令人鼓舞。在I/II期人体临床试验中，每天两次给药100 mg TMC120-R147681导致一周内病毒载量平均降低1.5 log10（约30倍）。在试验期间，没有观察到HIV-1 RT中出现耐药性突变，这对于这种类型的抑制剂来说是前所未有的。在整个开发过程中，我们已经确定了HIV-1 RT先导化合物的晶体结构，这些结构已用于指导理解抑制剂活性的三维决定因素以及与耐药突变的相互作用。该过程中使用的大多数结构都是使用CHESS F1光束线的辐射确定的。利用MacCHESS的资源从实验室获得的其他结果包括确定人类鼻病毒的结构（Ding等人，出版中）：显示HIV-1 V3环片段的HIV-1嵌合病毒（也称为gp120包膜蛋白的“主要中和结构域”）和确定b淋巴细胞刺激因子（BlyS）的结构，BlyS是一种参与免疫反应调节的人类细胞因子（Oren等人，2002）。

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).