Peptide T

Last updated
Peptide T
Peptide T.svg
Names
IUPAC name
L-Alanyl-L-seryl-L-threonyl-L-threonyl-L-threonyl-L-asparaginyl-L-tyrosyl-L-threonine
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C35H55N9O16/c1-13(36)28(52)40-22(12-45)31(55)41-25(15(3)47)33(57)43-26(16(4)48)34(58)42-24(14(2)46)32(56)39-21(11-23(37)51)29(53)38-20(10-18-6-8-19(50)9-7-18)30(54)44-27(17(5)49)35(59)60/h6-9,13-17,20-22,24-27,45-50H,10-12,36H2,1-5H3,(H2,37,51)(H,38,53)(H,39,56)(H,40,52)(H,41,55)(H,42,58)(H,43,57)(H,44,54)(H,59,60)/t13-,14+,15+,16+,17+,20-,21-,22-,24-,25-,26-,27-/m0/s1
    Key: IWHCAJPPWOMXNW-LYKMMFCUSA-N
  • InChI=1/C35H55N9O16/c1-13(36)28(52)40-22(12-45)31(55)41-25(15(3)47)33(57)43-26(16(4)48)34(58)42-24(14(2)46)32(56)39-21(11-23(37)51)29(53)38-20(10-18-6-8-19(50)9-7-18)30(54)44-27(17(5)49)35(59)60/h6-9,13-17,20-22,24-27,45-50H,10-12,36H2,1-5H3,(H2,37,51)(H,38,53)(H,39,56)(H,40,52)(H,41,55)(H,42,58)(H,43,57)(H,44,54)(H,59,60)/t13-,14+,15+,16+,17+,20-,21-,22-,24-,25-,26-,27-/m0/s1
    Key: IWHCAJPPWOMXNW-LYKMMFCUBM
  • O=C(N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)O)[C@H](O)C)Cc1ccc(O)cc1)CC(=O)N)[C@H](O)C)[C@H](O)C)[C@H](O)C)CO)[C@@H](N)C
Properties
C35H55N9O16
Molar mass 857.872 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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. DAPTA was initially administered as a nasal spray, but this formulation was found to be unstable. A more stable oral form, called RAP-103, is a shorter pentapeptide derived from DAPTA. RAP-103 is a CCR2/CCR5 antagonist that protects synapses by blocking the synaptotoxic actions of oligomeric forms of amyloid beta [4] and alpha-synuclein. [5] , as well as HIV gp120, via a PrPc dependent pathway. Synapse loss underlies the cognitive losses attributed to these toxic proteins and the ensuing clinical conditions of AD, LBD, and HAND, which these peptide chemokine receptor antagonists may safely treat. In preclinical studies, RAP-103 has also been shown to prevent and reverse neuropathic pain [6] and to reduce opioid addiction liability. [7]

Contents

Peptide T has several positive effects related to HIV disease and Neuro-AIDS. [8] 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. [9] 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<0.05). Furthermore, twice as many DAPTA-treated patients improved, whereas twice as many placebo patients deteriorated (P=0.02). A sub-group analysis showed that DAPTA had a treatment effect and improved global cognitive performance (P=0.02) in the patients who had more severe cognitive impairment. [10]

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. [11] 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. [12] Elimination of viral reservoirs, such as the persistently infected monocytes or brain microglia, is an important treatment goal. [13]

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. [14] RAP-103 also blocks CCR8, [15] which may be important in neuropathic pain. [16] Inhibitors of CCR5, including DAPTA, [17] [18] prevent and reverse neurodegeneration and are therapeutic targets in stroke/brain injury [19] and dementia, such as in Parkinsons Disease. [20]

In the 2013 biographical film Dallas Buyers Club , [21] 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.[ citation needed ]

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. [22]

Related Research Articles

<span class="mw-page-title-main">Candace Pert</span> American neuroscientist (1946–2013)

Candace Beebe Pert was an American neuroscientist and pharmacologist who discovered the opioid receptor, the cellular binding site for endorphins in the brain.

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">CCR5</span> Immune system protein

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.

<span class="mw-page-title-main">CXCR4</span> Protein

C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.

<span class="mw-page-title-main">CCL2</span> Protein found in humans

The chemokine ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 tightly regulates cellular mechanics and thereby recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection.

<span class="mw-page-title-main">CCL5</span> Mammalian protein found in humans

Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome.

Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D.

Chemokine ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small glycoprotein that belongs to the CC chemokine family.

<span class="mw-page-title-main">CCL7</span> Mammalian protein found in Homo sapiens

Chemokine ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2.

<span class="mw-page-title-main">CCL8</span> Mammalian protein found in Homo sapiens

Chemokine ligand 8 (CCL8), also known as monocyte chemoattractant protein 2 (MCP2), is a protein that in humans is encoded by the CCL8 gene.

<span class="mw-page-title-main">Maraviroc</span> Antiretroviral drug

Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class.

CC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.

<span class="mw-page-title-main">CCR2</span> Mammalian protein found in humans

C-C chemokine receptor type 2 (CCR2 or CD192 is a protein that in humans is encoded by the CCR2 gene. CCR2 is a CC chemokine receptor.

<span class="mw-page-title-main">CCR1</span> Protein in humans

C-C chemokine receptor type 1 is a protein that in humans is encoded by the CCR1 gene.

<span class="mw-page-title-main">CCR3 (gene)</span> Protein-coding gene in humans

C-C chemokine receptor type 3 is a protein that in humans is encoded by the CCR3 gene.

<span class="mw-page-title-main">Broad-spectrum chemokine inhibitor</span> Drug class

A broad-spectrum chemokine inhibitor or BSCI is a type of experimental anti-inflammatory drug that inhibits the action of the pro-inflammatory proteins chemokines. Radiolabeling experiments performed by Dr. David Fox, University of Warwick, demonstrated the ability of the BSCI to bind and antagonize the somatostatin receptor 2 (SSTR2). This is a display of functional selectivity at the SSTR2 receptor. Functional selectivity is the effect of one ligand having one agonism when bound to the receptor and another ligand having a different agonism at that same receptor.

<span class="mw-page-title-main">NR58-3.14.3</span> Chemical compound

NR58.3-14-3 is a cyclic peptide consisting of 11 D-amino acids. It is a broad-spectrum chemokine inhibitor and anti-inflammatory agent.

CCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the process by which HIV, the virus that causes AIDS, enters cells. Hence antagonists of this receptor are entry inhibitors and have potential therapeutic applications in the treatment of HIV infections.

<span class="mw-page-title-main">Cenicriviroc</span> Chemical compound

Cenicriviroc is an experimental drug candidate for the treatment of HIV infection and in combination with Tropifexor for non-alcoholic steatohepatitis. It is being developed by Takeda and Tobira Therapeutics.

A small proportion of humans show partial or apparently complete innate resistance to HIV, the virus that causes AIDS. The main mechanism is a mutation of the gene encoding CCR5, which acts as a co-receptor for HIV. It is estimated that the proportion of people with some form of resistance to HIV is under 10%.

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. Bibcode:1986PNAS...83.9254P. doi: 10.1073/pnas.83.23.9254 . PMC   387114 . 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. ↑ "RAP-103 inhibits amyloid-beta-induced synaptic toxicity". Biomedicines. 12 (1). 2023. doi: 10.3390/biomedicines12010093 . PMC   10813319 .
  5. ↑ "RAP-103 prevents alpha-synuclein-induced neurotoxicity". Cell Death & Disease. 15. 2024. doi:10.1038/s41419-024-06630-9.
  6. ↑ "The effects of RAP-103 on neuropathic pain". Pain. 152 (12): 2822–2831. 2011. doi:10.1016/j.pain.2011.09.022. PMID   22033364.
  7. ↑ Bongiovanni, A. R.; Zhao, P.; Inan, S.; Wiah, S.; Shekarabi, A.; Farkas, D. J.; Watson, M. N.; Wimmer, M. E.; Ruff, M. R.; Rawls, S. M. (2022). "RAP-103 reduces opioid addiction liability in animal models". Drug and Alcohol Dependence. 243. doi:10.1016/j.drugalcdep.2022.109556. PMC   9444981 . PMID   35843139.
  8. ↑ 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. Archived from the original on July 20, 2012.
  9. ↑ Villemagne VL, Phillips RL, Liu X, Gilson SF, Dannals RF, Wong DF, Harris PJ, Ruff M, Pert C, Bridge P, London ED (July 1996). "Peptide T and glucose metabolism in AIDS dementia complex". J. Nucl. Med. 37 (7): 1177–80. PMID   8965193.
  10. ↑ 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 (January 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.
  11. ↑ 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. S2CID   12925475.
  12. ↑ 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. S2CID   40797488.
  13. ↑ 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. doi:10.1189/jlb.68.3.345. PMID   10985250.
  14. ↑ Padi SSV; Shi, X. Q.; Zhao, Y. Q.; Ruff, M. R.; Baichoo, N.; Pert, C. B.; Zhang, J. (2012). "Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation". Pain. 153 (1): 95–106. doi:10.1016/j.pain.2011.09.022. PMID   22033364. S2CID   28310179.
  15. ↑ Noda, M.; Tomonaga, D.; Kitazono, K.; Yoshioka, Y.; Liu, J.; Rousseau, J. P.; Kinkead, R.; Ruff, M. R.; Pert, C. B. (2018). "Neuropathic pain inhibitor, RAP-103, is a potent inhibitor of microglial CCL1/CCR8". Neurochemistry International. 119: 184–189. doi:10.1016/j.neuint.2017.12.005. PMID   29248693. S2CID   23454214.
  16. ↑ Zychowska, M.; Rojewska, E.; Piotrowska, A.; Kreiner, G.; Nalepa, I.; Mika, J. (2017). "Spinal CCL1/CCR8 signaling interplay as a potential therapeutic target - Evidence from a mouse diabetic neuropathy model". International Immunopharmacology. 52: 261–271. doi:10.1016/j.intimp.2017.09.021. PMID   28961489. S2CID   25901496.
  17. ↑ Hill, J. M.; Mervis, R. F.; Avidor, R.; Moody, T. W.; Brenneman, D. E. (1993). "HIV envelope protein-induced neuronal damage and retardation of behavioral development in rat neonates". Brain Research. 603 (2): 222–233. doi:10.1016/0006-8993(93)91241-j. PMID   8461978. S2CID   29222082.
  18. ↑ Socci, D. J.; Pert, C. B.; Ruff, M. R.; Arendash, G. W. (1996). "Peptide T prevents NBM lesion-induced cortical atrophy in aged rats". Peptides. 17 (5): 831–837. doi: 10.1016/0196-9781(96)00106-4 . PMID   8844774. S2CID   28570986.
  19. ↑ 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. (2019). "CCR5 is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury". Cell. 176 (5): 1143–1157.e13. doi:10.1016/j.cell.2019.01.044. PMC   7259116 . PMID   30794775.
  20. ↑ Mondal, S.; Rangasamy, S. B.; Roy, A.; Dasarathy, S.; Kordower, J. H.; Pahan, K. (2019). "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. doi:10.4049/jimmunol.1800587. PMC   6824976 . PMID   31043478.
  21. ↑ Dallas Buyers Club. Dir. Jean-Marc Vallée. Perf. Matthew McConaughey. Truth Entertainment, Voltage Pictures; Focus Features (US), 2013.
  22. ↑ Marcusson, Jan. "Peptide T a new treatment for psoriasis? A study of nine patients". PMID   1685829. Archived from the original on 2023-12-06. Retrieved 2023-12-06. Alt URL
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