Neurokinin-1R (SP Receptor)Antagonists for HIV Therapy

Steven D. Douglas, MDNovember 16, 2005

Neurokinin-1 receptor antagonist(s) substance P – preferring potential therapeutic pathways

1. Anti-viral HIV – In vitro and in vivoCellular mechanism

2. Immunomodulatory

3. Anti-depressive behavior

Projects and CoresProjects: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 AdministrationS. Douglas, Dir

P1W-Z Ho, PI

P3A. Lackner, PI

P2S. Douglas, PI

P4P. Tebas, PI

Core BVirus Susceptibility

J Lathey, DirSeracare Bioservices

(Private Sector Partner)

Basic Pre-clinical/clinical

IPCP Organizational Schema

Core C Biostatistics and Pharmacology

A. Cnaan, Dir.J. Barrett, Co-Dir.

Internal Advisory Committee1. 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 Research6. 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

An

tivira

lIm

munom

odulatory

CellularMechanism

Substance P

(Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2)

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 Medicine 249 (1), 27-40.