Peptide T Explained

Peptide T is an HIV entry inhibitor discovered in 1986 by Candace Pert and Michael Ruff, a US neuroscientist and immunologist.[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.[5] 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.[6]

An 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.[7] 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.[8] Elimination of viral reservoirs, such as the persistently infected monocytes or brain microglia, is an important treatment goal.[9]

Peptide T clinical development was stopped due to the propensity of the liquid nasal spray to lose potency upon storage and shifted to its shorter oral analog, the pentapeptide CCR2/CCR5 antagonist RAP-103 (Receptor Active Peptide) for neuropathic pain and neurodegeneration.[10] RAP-103 also blocks CCR8,[11] which may be important in neuropathic pain.[12] Inhibitors of CCR5, including DAPTA,[13] [14] prevent and reverse neurodegeneration and are therapeutic targets in stroke/brain injury[15] and dementia, such as in Parkinsons Disease.[16]

Popular culture

In the 2013 biographical film Dallas Buyers Club,[17] 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.

Psoriasis

A 1991 Stockholm study with 9 patients and no control group found that even small doses of 2 mg of Peptide T given intravenously in 500 ml saline for 28 days, once a day, alleviate psoriasis symptoms by more than 50% in 5 patients, 3 months after the treatment ended.[18]

Notes and References

  1. Pert CB . 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 . Dec 1986 . 3097649 . 387114 . 10.1073/pnas.83.23.9254 . vanc. Hill JM . Ruff MR . 3 . Berman . RM . Robey . WG . Arthur . LO . Ruscetti . FW . Farrar . WL. 1986PNAS...83.9254P . free .
  2. Polianova MT, Ruscetti FW, Pert CB, Ruff MR . Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA) . Antiviral Res. . 67 . 2 . 83–92 . Aug 2005 . 16002156 . 10.1016/j.antiviral.2005.03.007 .
  3. Ruff MR . Peptide T inhibits HIV-1 infection mediated by the chemokine receptor-5 (CCR5) . Antiviral Res. . 52 . 1 . 63–75 . Oct 2001 . 11530189 . 10.1016/S0166-3542(01)00163-2 . vanc. Melendez-Guerrero LM . Yang QE . 3 . Ho . Wen-Zhe . Mikovits . Judy W. . Pert . Candace B. . Ruscetti . Francis A..
  4. Ruff MR, Polianova M, Yang QE, Leoung GS, Ruscetti FW, Pert CB . Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors . Curr. HIV Res. . 1 . 1 . 51–67 . Jan 2003 . 15043212 . 10.2174/1570162033352066.
  5. Villemagne VL, Phillips RL, Liu X, Gilson SF, Dannals RF, Wong DF, Harris PJ, Ruff M, Pert C, Bridge P, London ED . Peptide T and glucose metabolism in AIDS dementia complex . J. Nucl. Med. . 37 . 7 . 1177–80 . July 1996 . 8965193 .
  6. Heseltine PN, Goodkin K, Atkinson JH, Vitiello B, Rochon J, Heaton RK, Eaton EM, Wilkie FL, Sobel E, Brown SJ, Feaster D, Schneider L, Goldschmidts WL, Stover ES . Randomized double-blind placebo-controlled trial of peptide T for HIV-associated cognitive impairment . Arch. Neurol. . 55 . 1 . 41–51 . January 1998 . 9443710 . 10.1001/archneur.55.1.41 .
  7. Goodkin K . 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 . Jun 2006 . 16877299 . 10.1080/13550280600827344 . vanc. Vitiello B . Lyman WD . 3 . Asthana . Deshratn . Atkinson . J Hampton . Heseltine . Peter NR . Molina . Rebeca . Zheng . Wenli . Khamis . Imad . 12925475 .
  8. Polianova MT . Antiviral and immunological benefits in HIV patients receiving intranasal peptide T (DAPTA) . Peptides . 24 . 7 . 1093–8 . Jul 2003 . 14499289 . 10.1016/S0196-9781(03)00176-1 . vanc. Ruscetti FW . Pert CB . 3 . Tractenberg . RE . Leoung . G . Strang . S . Ruff . MR. 40797488 .
  9. Crowe SM, Sonza S . 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 . Sep 2000 . 10985250 .
  10. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. 22033364. 2012. Padi SSV. Shi. X. Q.. Zhao. Y. Q.. Ruff. M. R.. Baichoo. N.. Pert. C. B.. Zhang. J.. Pain. 153. 1. 95–106. 10.1016/j.pain.2011.09.022. 28310179.
  11. Neuropathic pain inhibitor, RAP-103, is a potent inhibitor of microglial CCL1/CCR8. 29248693. 2018. Noda. M.. Tomonaga. D.. Kitazono. K.. Yoshioka. Y.. Liu. J.. Rousseau. J. P.. Kinkead. R.. Ruff. M. R.. Pert. C. B.. Neurochemistry International. 119. 184–189. 10.1016/j.neuint.2017.12.005. 23454214.
  12. Spinal CCL1/CCR8 signaling interplay as a potential therapeutic target - Evidence from a mouse diabetic neuropathy model. 28961489. 2017. Zychowska. M.. Rojewska. E.. Piotrowska. A.. Kreiner. G.. Nalepa. I.. Mika. J.. International Immunopharmacology. 52. 261–271. 10.1016/j.intimp.2017.09.021. 25901496.
  13. HIV envelope protein-induced neuronal damage and retardation of behavioral development in rat neonates. 8461978. 1993. Hill. J. M.. Mervis. R. F.. Avidor. R.. Moody. T. W.. Brenneman. D. E.. Brain Research. 603. 2. 222–233. 10.1016/0006-8993(93)91241-j. 29222082.
  14. Peptide T prevents NBM lesion-induced cortical atrophy in aged rats. 8844774. 1996. Socci. D. J.. Pert. C. B.. Ruff. M. R.. Arendash. G. W.. Peptides. 17. 5. 831–837. 10.1016/0196-9781(96)00106-4. 28570986. free.
  15. 30794775. 2019. Joy. M. T.. Ben Assayag. E.. Shabashov-Stone. D.. Liraz-Zaltsman. S.. Mazzitelli. J.. Arenas. M.. Abduljawad. N.. Kliper. E.. Korczyn. A. D.. Thareja. N. S.. Kesner. E. L.. Zhou. M.. Huang. S.. Silva. T. K.. Katz. N.. Bornstein. N. M.. Silva. A. J.. Shohami. E.. Carmichael. S. T.. CCR5 is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury. Cell. 176. 5. 1143–1157.e13. 10.1016/j.cell.2019.01.044. 7259116.
  16. 31043478. 2019. Mondal. S.. Rangasamy. S. B.. Roy. A.. Dasarathy. S.. Kordower. J. H.. Pahan. K.. Low-Dose Maraviroc, an Antiretroviral Drug, Attenuates the Infiltration of T Cells into the Central Nervous System and Protects the Nigrostriatum in Hemiparkinsonian Monkeys. Journal of Immunology. 202. 12. 3412–3422. 10.4049/jimmunol.1800587. 6824976.
  17. Dallas Buyers Club. Dir. Jean-Marc Vallée. Perf. Matthew McConaughey. Truth Entertainment, Voltage Pictures; Focus Features (US), 2013.
  18. Web site: Marcusson . Jan . Peptide T a new treatment for psoriasis? A study of nine patients. . 2023-12-06 . https://pdfhost.io/v/cf6nKzKuC_amandersson71479483 . 2023-12-06.

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