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).
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