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Substance P Receptor (Neurokinin-1R) Antagonists as Therapeutic Agents in HIV

Substance P Receptor (Neurokinin-1R) Antagonists as Therapeutic Agents in HIV. Steven D. Douglas, MD August 4, 2004. Overall Goal. To demonstrate the mechanism and activity of neurokinin-1R (substance P) antagonists as antiviral agents in HIV.

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Substance P Receptor (Neurokinin-1R) Antagonists as Therapeutic Agents in HIV

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  1. Substance P Receptor (Neurokinin-1R) Antagonists as Therapeutic Agents in HIV Steven D. Douglas, MD August 4, 2004

  2. Overall Goal To demonstrate the mechanism and activity of neurokinin-1R (substance P) antagonists as antiviral agents in HIV.

  3. Neurokinin-1R 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

  4. Projects and Cores • Projects: • Anti-HIV Mechanisms of Neurokinin-1 Receptor • (NK-1R) Antagonists– Ho • 2. Cellular Mechanisms and Interaction of Neurokinin-1 • Receptor (NK-1R) Antagonists and HIV Co-Receptors • CCR5 and CXCR4– Douglas, Kilpatrick • 3. SIV models of neurobehavioral, antiviral, and • immunomodulatory SP antagonist(s) effects – Lackner, • Baker • 4. Human Studies of Neurokinin-1 Receptor (NK-1R) • Antagonists in HIV-1 - Tebas

  5. Projects and Cores • Cores: • Administrative – Douglas • B. HIV Antiretroviral Drug Susceptibility and • Drug Interactions – Lathey • C. Biostatistics and Pharmacology- Cnaan

  6. 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 BBI (Private Sector Partner) Core C Biostatistics and Pharmacology A. Cnaan, Dir.

  7. Private Sector Partner Name: Boston Biomedica, Inc. Gaithersburg, MD PI: Dr. Janet Lathey HIV Antiretroviral Drug Susceptibility and Drug Interactions Core

  8. Biotech Overview • The research and development arm of the Company for Molecular Biology, Virology and Immunology • Experienced Scientific Staff consisting of 9 PhD’s and more than 50 scientists • Provides a variety of products and services to BBI operating units and other outside customers • Specialty reagents and molecular and cellular biology services • Blood and tissue processing and repository services • Clinical trials for domestic and foreign test kit and device manufacturers • Services typically provided under multi-year contracts • Services focused in advanced biomedical research areas

  9. Virology Services Available for Clinical Trials of Therapeutics • HIV Antigen Detection and Quantitation • HIV Culture and Viral Isolation • Titration of Infectious Virus • Drug Susceptibility Assays • Viral Nucleic Acid Isolation • Viral Nucleic Acid Quantitation

  10. Collaborative Resources • CFAR Cores – Douglas, Tebas, Lackner (Hoxie, Gonzalez) • AACTU – Tebas (PI) • HUP GCRC – Tebas • HPTN – Douglas, Metzger • PPACTU – Douglas (PI) • CHOP Cores – Molecular, Flow Cytometry, • Biostatistics, Protein, Nucleic Acid

  11. Background and Prior NIMH-supported Work by Investigators MH49981

  12. CNS

  13. 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.

  14. Biological Activities of SP • A potent neurotransmitter and neuromodulator. Interactions with other neurotransmitters in the brain. • Transmission of painful stimuli from periphery. • Control blood flow (vasodilatation). • Gastrointestinal motility, enteric secretion and absorption. • A potent mediator of neuroimmunoregulation. Activation of cells of the immune system and participation of inflammatory process. • A hematopoietic modulator.

  15. Tachykinin Family Tachykinin PPT-A PPT-B Substance P Neurokinin A Neurokinin B NK-1R: SP>NKA>NKB NK-2R: NKA>NKB>SP NK-3R: NKB>NKA>SP

  16. Human Immune Cells Express Substance P and Its Receptor • Ho, et al 1997. J. Immunol. 159:5654-60. • Lai, et al 1998. J. Neuroimmunol. 86:80-6. • Lai, et al 2000. Neuroscience 101:1137-44. • Li, et al 2000. J. Hematotherapy Stem Cell Res. 9:445. • Lai, et al 2002. Clin. Diagn. Lab. Immunol. 9:138-43. MH49981

  17. SP Induces Activation and Replication of HIV • Ho, et al 1996. AIDS Res. Hum. Retroviruses 12:195-99. • Li, et al 2001. J. Neuroimmunol. 121:67-75. • Lai, et al 2001. Proc. Natl. Acad. Sci. USA. 98:3970-75. • Ho, et al 2002. FASEB J. 16:616-18. MH49981

  18. SP Receptor Antagonists Inhibit HIV-1 InfectionLai,et al 2001. Proc. Natl. Acad. Sci. USA. 98:3970-75.

  19. Neurokinin-1 receptor (NK-1R) antagonists • Peptide and Non-peptide • NK-1R, dual, and pan-NK • Classification (groups): • Diamines • Amino-ethers • Perhydroisoindoles • Benzylpiperidine amides • Quinoline and napthyridine amides • Trytophan analogues

  20. Neurokinin-1 receptor (NK-1R) antagonists Peptide: Spantide-1 (Peninsula)(1985) - Full length SP analog Spantide-2,3 - Truncated C-terminal analogs (6-8 aa)

  21. Neurokinin-1 receptor (NK-1R) antagonists Non-Peptide: CP-96,345 (1991) Pfizer – quinuclidine residue - benzhydryl “double-ring” motif CJ-11,974 Pfizer – improved bioavailability RP-67580 – perhydroisoindole family L733060 Merck – piperidine Aprepitant(Emend) MK-869 – morpholine acetyl - benzylic methyl group fluorine - decreases oxidative metabolism

  22. Rationale for Clinical Development of Substance P Antagonists in Depression • Substance P (SP) is released in response to stressful stimuli • SP is localized in regions controlling affective behavior • (colocalization with select NA and 5-HT neurons in specific • pathways) • Amygdala • Limbic areas • Monoamine nuclei (raphe, locus ceruleus) • Hypothalamus • SP binding to NK-1 receptors elicits mood and emotional • changes Kramer MS et al. Science 281:1640, 1998

  23. Structural Formula of Emend (Aprepitant) Empirical formula – C23H21F7N4O3

  24. SP receptor antagonist (Emend) potently inhibits HIV (Bal) replication of human macrophages

  25. Overview Projects 1 and 2 - Basic Projects: 1. Will determine in vitro efficacy, antiviral specificity 2. Will determine cellular mechanism of action and specificity 3. With private sector partner (Boston Biomedica,Inc., Dr. Janet Lathey), will determine synergy with known HIV antivirals 4. Will guide selection of optimal neurokinin-1R antagonist for preclinical/clinical a. Specificity b. Potency c. Toxicity

  26. Overview Project 3 - Pre-clinical Non-Human Primate Project: 1. Will determine safety and pharmacokinetics 2. Will determine anti-SIV activity 3. Will evaluate effects on behavior

  27. Overview Project 4 - Human Studies of Neurokinin-1 Receptor (NK-1R) Antagonists in HIV-1 : 1. Will determine safety 2. Will determine antiviral HIV activity – Phase 1B clinical trial 3. Will determine pharmacokinetics and viral dynamics 4. Will evaluate immunomodulatory effects 5. Will evaluate depressive behavior effects

  28. Safety issues to be addressed (Aprepitant and other NK-1R antagonists) • Viral resistance/escape • - Projects 1, 3, 4; Core B • Increased SIV/HIV viral burden • - Projects 3, 4 • Immunosuppression – impaired immune modulation • - Projects 2, 3, 4 • Behavioral changes • - Projects 3, 4 • Negative interaction with retrovirals • - Projects 3; Core B

  29. Interactions Between Projects Cellular Mechanism P2 P1 Antiviral Antiviral Antiviral Immunomodulatory Immunomodulatory P3 P4 Safety

  30. PI and CI R01 List Douglas – R01 MH49981, R01 AA13547, U01 AI32921 Ho – R01 DA12815, R21 DA16022 Kilpatrick – R01 GM64552 Lackner – R01 NS30769, R01 MH61192, R01 DK50550 Tebas – U01 AI32783 Evans – R01 MH44618, R25 MH60490, R01 MH067501 Cnaan – P01 CA097323, U01 NS045803 Barrett – U01 Orange – K08 AI055602

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