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POSTDOCTORAL ASSOCIATE OR RESEARCH FACULTY POSITIONS AVAILABLE: STRUCTURE-BASED DRUG AND VACCINE DESIGN, STRUCTURAL STUDIES OF PROTEINS AND VIRUSES RELEVANT TO HIV/AIDS AND OTHER HUMAN DISEASES Our laboratory uses diverse tools and approaches from chemical, structural, and molecular biology to study the molecular processes and mechanisms underlying infectious disease, and to apply insights learned to structure-based design of drugs and vaccines. Positions are available for highly motivated researchers with a strong background in crystallography, chemistry, biochemistry, molecular biology, or virology. Each project involves cooperation with team members within our group and also with outside scientific collaborators. Projects include: (1) Structural studies of HIV-1 reverse transcriptase (RT) and drug-resistant mutants with and without bound nucleic acids (RNA/DNA and DNA/DNA template-primers) and inhibitors. Recent progress has included i) the successful design of novel HIV-1 RT inhibitors that are now in advanced clinical trials, and ii) systematic engineering of HIV-1 RT yielding constructs diffracting X-rays to 1.8 Å resolution. Among key areas of current emphasis are i) design and development of inhibitors of the RNase H activity of HIV-1 RT as potential anti-AIDS therapeutics, ii) experimental and virtual screening of drug-like fragments for binding to multiple sites on HIV-1 RT, iii) buildup of novel potential drugs starting from the fragments, and iv) further investigation of the mechanisms of resistance to nucleoside and non-nucleoside RT inhibitors. HIV-1 RT is a crucial drug target and a fascinating system for study at many levels. (2) Structural studies of multisubunit bacterial RNA polymerase (RNAP) with bound nucleic acids and inhibitors. RNAP is the enzyme responsible for catalyzing transcription in all living cells. We are studying bacterial RNAP structure with a focus on developing novel antibiotics for treating infections caused by multidrug resistant bacteria. We have discussed several novel inhibitor-binding sites and are continuing crystallographic investigation in parallel with computational design and synthesis of new analogs. RNAPs from several thermophilic and mesophilic species are being pursued. With mass > 400 kDa, multisubunit RNAPs are challenging subjects for structural elucidation, but their importance as drug targets and central role in biology make for a very rich system of study. (3) AIDS vaccine development: Human rhinoviruses are being engineered to display broadly reactive immunogens from HIV in diverse conformations. Combinatorial libraries of chimeric viruses are immunoselected with neutralizing HIV antibodies to isolate viruses with the most effectively reconstructed foreign immunogens. We have reconstructed V3 loop sequences and the gp41 2F5 epitope, both epitopes of which have been able to successfully elicit HIV-neutralizing responses in guinea pigs. Additional libraries will focus on the gp41 membrane-proximal region and CCR5 sequences. Structures of the human rhinovirus:HIV chimeras and complexes with antibody Fab fragments are being investigated by crystallography and cryo-EM with a long-term goal of devising approaches for structure-based design of vaccines. AA/EOE, m/f/h/v. Send CV and names and addresses of three references to: Eddy Arnold, [EMAIL PROTECTED]; Phone: (732) 235-5323 For vaccine-related inquiries, send information to Gail Ferstandig Arnold, [EMAIL PROTECTED]; Phone: (732) 235-4343. -- Professor Eddy Arnold Center for Advanced Biotechnology and Medicine Rutgers University Department of Chemistry and Chemical Biology 679 Hoes Lane Piscataway, NJ 08854 Phone: 732-235-5323 FAX: 732-235-5788 http://faculty.umdnj.edu/cabm/faculty_arnold.asp
