Neurokinin-1R (SP Receptor) Antagonists for HIV Therapy Steven D. Douglas, MD November 16, 2005

Neurokinin-1 receptor antagonist(s) substance P – preferring potential therapeutic pathways 1. Anti-viral HIV – In vitro and in vivo Cellular mechanism 2. Immunomodulatory 3. Anti-depressive behavior

Projects and Cores Projects: 1.NK-1R Antagonists – Anti-HIV Mechanisms – Ho 2. NK-1R Antagonists – Cellular and Molecular Mechanisms – Douglas, Kilpatrick, Lai 3. Substance P and NK-1R Antagonists in Simian AIDS – Lackner, Baker 4. Human Studies of NK-1R Antagonists in HIV-1 – Tebas, Orange

Projects and Cores Cores: A.Administrative – Douglas, Tuluc B. HIV Antiretroviral Drug Susceptibility and Drug Interactions – Lathey C. Biostatistics and Pharmacology – Cnaan, Barrett

Internal Advisory Board External Advisory Board Core A Administration S. Douglas, Dir P1 W-Z Ho, PI P3 A. Lackner, PI P2 S. Douglas, PI P4 P. Tebas, PI Core B Virus Susceptibility J Lathey, Dir Seracare Bioservices (Private Sector Partner) BasicPre-clinical/clinical IPCP Organizational Schema Core C Biostatistics and Pharmacology A. Cnaan, Dir. J. Barrett, Co-Dir.

Internal Advisory Committee 1.Dr. Peter Adamson, Associate Professor of Pediatrics; Chief, Div. of Clinical Pharmacology and Therapeutics (CHOP) 2. Dr. David F. Dinges, Professor of Psychology in Psychiatry; Chief, Division of Sleep and Chronobiology (UPenn) 3. Dr. Jonas Ellenberg, Professor of Biostatistics (UPenn) 4. Dr. Francisco Gonzalez-Scarano, Professor and Chair, Department of Neurology (UPenn) 5. Dr. James A. Hoxie, Professor of Medicine, Principal Investigator of Penn/CHOP/Wistar Center for AIDS Research 6. Dr. Mark Kramer, Professor of Psychiatry (UPenn) 7. Dr. David Pleasure, Professor of Neurology (CHOP) 8. Dr. Rita J. Valentino, Research Prof. of Pediatrics (CHOP)

External Advisory Committee 1.Dr. Howard Fox, Professor of Neuropharmacology, The Scripps Research Institute 2. Dr. Avindra Nath, Professor of Neurology; Director of Neuroimmunology and Neurological Infections, Johns Hopkins Medicine 3. Dr. Janice Clements, Professor and Director, Comparative Medicine, Johns Hopkins Medicine

Interactions Between Projects P1 P4P3 P2 Antiviral Immunomodulatory Safety Antiviral Immunomodulatory Cellular Mechanism

Substance P ( Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 )

SP, described by von Euler and Gaddum in 1931, was the first neuropeptide to be identified. SP is a neuropeptide comprised of 11 amino acid with a wide-spread distribution in the central and peripheral nervous systems (Chang and Leeman, 1970, 1971). SP belongs to the tachykinin family that includes SP, neurokinin A (SK), and neurokinin B.

Differential binding sites for substance P and the nonpeptide antagonist CP-96,345 in the NK1 receptor. Hokfelt at al. Journal of Internal Medicine 249 (1),