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: • 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: • Administrative – Douglas, Tuluc • B. HIV Antiretroviral Drug Susceptibility • and Drug Interactions – Lathey • C. Biostatistics and Pharmacology– Cnaan, Barrett
IPCP Organizational Schema Core A Administration S. Douglas, Dir Internal Advisory Board External Advisory Board Basic Pre-clinical/clinical P1 W-Z Ho, PI P2 S. Douglas, PI P3 A. Lackner, PI P4 P. Tebas, PI Core B Virus Susceptibility J Lathey, Dir Seracare Bioservices (Private Sector Partner) Core C Biostatistics and Pharmacology A. Cnaan, Dir. J. Barrett, Co-Dir.
Internal Advisory Committee • 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 • 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 Cellular Mechanism P2 P1 Antiviral Antiviral Antiviral Immunomodulatory Immunomodulatory P3 P4 Safety
Substance P(Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) • 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 Medicine249 (1), 27-40.