Peptide T

Peptide T
Names
IUPAC name
L-Alanyl-L-seryl-L-threonyl-L-threonyl-L-threonyl-L-asparaginyl-L-tyrosyl-L-threonine
Identifiers
106362-32-7 YesY
3D model (Jmol) Interactive image
ChemSpider 66081
PubChem 73352
UNII 05DYM3ZS1X YesY
Properties
C35H55N9O16
Molar mass 857.87 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Peptide T is an HIV entry inhibitor discovered in 1986 by researchers at the National Institutes of Health in the United States.[1] Peptide T, and its modified analog Dala1-peptide T-amide (DAPTA), a drug in clinical trials, is a short peptide derived from the HIV envelope protein gp120 which blocks binding[2] and infection[3] of viral strains which use the CCR5 receptor to infect cells.

Peptide T has several positive effects related to HIV disease and Neuro-AIDS.[4] A FDG-PET neuro-imaging study in an individual with AIDS dementia who completed a 12-wk treatment with intranasal DAPTA, showed remission in 34 out of 35 brain regions after treatment. (PMID 8965193). A placebo-controlled, three site, 200+ patient NIH-funded clinical trial, which focused on neurocognitive improvements, was conducted between 1990 and 1995. The results showed that DAPTA was not significantly different from placebo on the study primary end points. However, 2 of 7 domains, abstract thinking and speed of information processing, did show improvement in the DAPTA group (p<.05). Furthermore, twice as many DAPTA-treated patients improved, whereas twice as many placebo patients deteriorated (P=.02). A sub-group analysis showed that DAPTA had a treatment effect and improved global cognitive performance (P=.02) in the patients who had more severe cognitive impairment.[5]

A long-delayed analysis of antiviral effects from the 1996 NIH study showed peripheral viral load (combined plasma and serum) was significantly reduced in the DAPTA-treated group.[6] An eleven-person study for peptide T effects on cellular viral load showed reductions in the persistently infected monocyte reservoir to undetectable levels in most of the patients.[7] Elimination of viral reservoirs, such as the monocytes, is an important treatment goal.[8] DAPTA has been shown to substantially suppress brain inflammation and block proinflammatory cytokine signaling pathways in a small animal model of Alzheimer's disease.[9]

An orally administered analog of Peptide T/DAPTA prevented neuropathic pain from developing, or reversed it once it had occurred, (animals) by blocking chemokine receptors CCR2 and CCR5, microglial activation, the infiltration of monocytes into spinal cord, and inhibiting the inflammatory cytokines evoked by peripheral nerve injury that causes chronic pain. Peptide T/DAPTA has anti-inflammatory and neuroprotective actions which may underlie the described cognitive benefits and suggests uses in brain injuries and neurodegenerative diseases.(See PMID 22033364, PMID 19034668, PMID 23147416, PMID 24316469).

As of 2015, Peptide T is not currently available as a treatment in any country.

In the biographical film drama Dallas Buyers Club,[10] protagonist Ron Woodroof (Matthew McConaughey) promotes the use of injected peptide T as a treatment for HIV/AIDS and Alzheimer's Disease and sues the FDA over their efforts to limit his ability to use Peptide T, as it was an unapproved medicine. Additional information on Woodroof's court challenge to the FDA related to his obtaining access to Peptide T can be found in the article by Marsha Cohen in Hastings Constitutional Law Quarterly (vol.18:471) Cohen, 1991. Woodroof's challenge was in part responsible for the 1987 revisions to the FDA investigational drug regulations that expanded access to experimental drugs for patients with serious diseases with no alternative therapies.

References

  1. ↑ Pert CB, Hill JM, Ruff MR, et al. (Dec 1986). "Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T4 in brain potently inhibit human immunodeficiency virus receptor binding and T-cell infectivity". Proc Natl Acad Sci USA. 83 (23): 9254–8. doi:10.1073/pnas.83.23.9254. PMC 387114Freely accessible. PMID 3097649.
  2. ↑ Polianova MT, Ruscetti FW, Pert CB, Ruff MR (Aug 2005). "Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA)". Antiviral Res. 67 (2): 83–92. doi:10.1016/j.antiviral.2005.03.007. PMID 16002156.
  3. ↑ Ruff MR, Melendez-Guerrero LM, Yang QE, et al. (Oct 2001). "Peptide T inhibits HIV-1 infection mediated by the chemokine receptor-5 (CCR5)". Antiviral Res. 52 (1): 63–75. doi:10.1016/S0166-3542(01)00163-2. PMID 11530189.
  4. ↑ Ruff MR, Polianova M, Yang QE, Leoung GS, Ruscetti FW, Pert CB (Jan 2003). "Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors". Curr HIV Res. 1 (1): 51–67. doi:10.2174/1570162033352066. PMID 15043212.
  5. ↑ Heseltine PN, Goodkin K, Atkinson JH, et al. (Jan 1998). "Randomized double-blind placebo-controlled trial of peptide T for HIV-associated cognitive impairment". Arch Neurol. 55 (1): 41–51. doi:10.1001/archneur.55.1.41. PMID 9443710.
  6. ↑ Goodkin K, Vitiello B, Lyman WD, et al. (Jun 2006). "Cerebrospinal and peripheral human immunodeficiency virus type 1 load in a multisite, randomized, double-blind, placebo-controlled trial of D-Ala1-peptide T-amide for HIV-1-associated cognitive-motor impairment". J Neurovirol. 12 (3): 178–89. doi:10.1080/13550280600827344. PMID 16877299.
  7. ↑ Polianova MT, Ruscetti FW, Pert CB, et al. (Jul 2003). "Antiviral and immunological benefits in HIV patients receiving intranasal peptide T (DAPTA)". Peptides. 24 (7): 1093–8. doi:10.1016/S0196-9781(03)00176-1. PMID 14499289.
  8. ↑ Crowe SM, Sonza S (Sep 2000). "HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication". J Leukoc Biol. 68 (3): 345–50. PMID 10985250.
  9. ↑ Rosi, S; Pert, C; Ruff, M; McGanngramling, K; Wenk, G (2005). "Chemokine receptor 5 antagonist -Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease". Neuroscience. 134 (2): 671–6. doi:10.1016/j.neuroscience.2005.04.029. PMID 15979806.
  10. ↑ Dallas Buyers Club. Dir. Jean-Marc Vallée. Perf. Matthew McConaughey. Truth Entertainment, Voltage Pictures; Focus Features (US), 2013.
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