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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 与比利时扬森研究基金会分子设计中心的保罗·扬森及其同事进行的基于结构的药物设计项目长期合作，已经产生了一些非常令人兴奋的潜在艾滋病治疗药物。我们研究了HIV-1RT的一系列非核苷抑制剂(NNRTI)之间的相互作用，通过确定过程中的许多类似物的结构。使用MacCHESS对这一进程是绝对必要的。合成了多种结构相关的NNRTI类化合物，导致了二苯胺嘧啶(DAPY)类似物的发现(Ludovici等人，2001年，3篇论文)。结合针对包含临床相关突变的HIV变异体的抗病毒筛选、代谢研究和三维结构-活性关系，确定TMC120-R147681和TMC125-R165335是高效的艾滋病毒复制广谱抑制剂。对这些化合物进行的初步人体研究非常令人鼓舞。在I/II期人体临床试验中，患者每天服用两次100毫克的TMC120-R147681，一周内病毒载量平均减少1.5log10(约30倍)。在试验过程中没有观察到HIV-1RT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，我们用HIV-1 RT确定了先导化合物的晶体结构，这些结构被用来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。这一过程中使用的大部分结构是使用国际象棋F1光束线的辐射确定的。该实验室利用MacCHESS的资源获得的其他结果包括：人鼻病毒：HIV-1嵌合病毒的结构(Ding等人，出版社中)，该病毒显示HIV-1V3环的一段(也称为gp120包膜蛋白的“主要中和域”)，以及B淋巴细胞刺激因子(BLyS)的结构，B淋巴细胞刺激因子是一种参与免疫反应调节的人类细胞因子(Oren等人，2002年)。

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).