:Peptide T

{{Short description|Chemical compound CCR5 CCR2 CCR8 antagonist oral peptide treatment for HIV TBI dementia}}

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| ImageFile = Peptide T.svg

| ImageSize = 250px

| IUPACName = L-Alanyl-L-seryl-L-threonyl-L-threonyl-L-threonyl-L-asparaginyl-L-tyrosyl-L-threonine

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| CASNo = 106362-32-7

| CASNo_Ref = {{cascite|correct|CAS}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 05DYM3ZS1X

| PubChem = 73352

| ChemSpiderID = 66081

| SMILES = 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

| 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

| InChIKey = IWHCAJPPWOMXNW-LYKMMFCUBM

| StdInChI = 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

| StdInChIKey = IWHCAJPPWOMXNW-LYKMMFCUSA-N

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|Section2={{Chembox Properties

| C=35 | H=55 | N=9 | O=16

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Peptide T is an HIV entry inhibitor discovered in 1986 by Candace Pert and Michael Ruff, a US neuroscientist and immunologist.{{cite journal |author=Pert CB |title=Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T4 in brain potently inhibit human immunodeficiency virus receptor binding and T-cell infectivity |journal=Proc Natl Acad Sci USA |volume=83 |issue=23 |pages=9254–8 |date=Dec 1986 |pmid=3097649 |pmc=387114 |doi=10.1073/pnas.83.23.9254 |name-list-style=vanc|author2=Hill JM |author3=Ruff MR |display-authors=3 |last4=Berman |first4=RM |last5=Robey |first5=WG |last6=Arthur |first6=LO |last7=Ruscetti |first7=FW |last8=Farrar |first8=WL|bibcode=1986PNAS...83.9254P |doi-access=free }} 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{{cite journal |vauthors=Polianova MT, Ruscetti FW, Pert CB, Ruff MR |title=Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA) |journal=Antiviral Res. |volume=67 |issue=2 |pages=83–92 |date=Aug 2005 |pmid=16002156 |doi=10.1016/j.antiviral.2005.03.007 }} and infection{{cite journal |author=Ruff MR |title=Peptide T inhibits HIV-1 infection mediated by the chemokine receptor-5 (CCR5) |journal=Antiviral Res. |volume=52 |issue=1 |pages=63–75 |date=Oct 2001 |pmid=11530189 |doi=10.1016/S0166-3542(01)00163-2 |name-list-style=vanc|author2=Melendez-Guerrero LM |author3=Yang QE |display-authors=3 |last4=Ho |first4=Wen-Zhe |last5=Mikovits |first5=Judy W. |last6=Pert |first6=Candace B. |last7=Ruscetti |first7=Francis A.}} 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{{cite journal |title=RAP-103 inhibits amyloid-beta-induced synaptic toxicity |journal=Biomedicines |volume=12 |issue=1 |year=2023 |doi=10.3390/biomedicines12010093|doi-access=free |pmc=10813319 }} and alpha-synuclein.{{cite journal |title=RAP-103 prevents alpha-synuclein-induced neurotoxicity |journal=Cell Death & Disease |volume=15 |year=2024 |doi=10.1038/s41419-024-06630-9}} , 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{{cite journal |title=The effects of RAP-103 on neuropathic pain |journal=Pain |volume=152 |issue=12 |pages=2822–2831 |year=2011 |doi=10.1016/j.pain.2011.09.022|pmid=22033364 }} and to reduce opioid addiction liability.{{cite journal |title=RAP-103 reduces opioid addiction liability in animal models |journal=Drug and Alcohol Dependence |volume=243 |year=2022 |doi=10.1016/j.drugalcdep.2022.109556|pmid=35843139 |last1=Bongiovanni |first1=A. R. |last2=Zhao |first2=P. |last3=Inan |first3=S. |last4=Wiah |first4=S. |last5=Shekarabi |first5=A. |last6=Farkas |first6=D. J. |last7=Watson |first7=M. N. |last8=Wimmer |first8=M. E. |last9=Ruff |first9=M. R. |last10=Rawls |first10=S. M. |pmc=9444981 }}

Peptide T has several positive effects related to HIV disease and Neuro-AIDS.{{cite journal |vauthors=Ruff MR, Polianova M, Yang QE, Leoung GS, Ruscetti FW, Pert CB |title=Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors |journal=Curr. HIV Res. |volume=1 |issue=1 |pages=51–67 |date=Jan 2003 |pmid=15043212 |url=http://www.bentham-direct.org/pages/content.php?CHR/2003/00000001/00000001/005AB.SGM |archive-url=https://archive.today/20120720214451/http://www.bentham-direct.org/pages/content.php?CHR/2003/00000001/00000001/005AB.SGM |url-status=usurped |archive-date=July 20, 2012 |doi=10.2174/1570162033352066|url-access=subscription }} 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.{{cite journal | vauthors = Villemagne VL, Phillips RL, Liu X, Gilson SF, Dannals RF, Wong DF, Harris PJ, Ruff M, Pert C, Bridge P, London ED | title = Peptide T and glucose metabolism in AIDS dementia complex | journal = J. Nucl. Med. | volume = 37 | issue = 7 | pages = 1177–80 | date = July 1996 | 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<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.{{cite journal | vauthors = 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 | title = Randomized double-blind placebo-controlled trial of peptide T for HIV-associated cognitive impairment | journal = Arch. Neurol. | volume = 55 | issue = 1 | pages = 41–51 | date = January 1998 | pmid = 9443710 | doi = 10.1001/archneur.55.1.41 | doi-access = }}

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.{{cite journal |author=Goodkin K |title=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 |journal=J. Neurovirol. |volume=12 |issue=3 |pages=178–89 |date=Jun 2006 |pmid=16877299 |doi=10.1080/13550280600827344 |name-list-style=vanc|author2=Vitiello B |author3=Lyman WD |display-authors=3 |last4=Asthana |first4=Deshratn |last5=Atkinson |first5=J Hampton |last6=Heseltine |first6=Peter NR |last7=Molina |first7=Rebeca |last8=Zheng |first8=Wenli |last9=Khamis |first9=Imad |s2cid=12925475 }} 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.{{cite journal |author=Polianova MT |title=Antiviral and immunological benefits in HIV patients receiving intranasal peptide T (DAPTA) |journal=Peptides |volume=24 |issue=7 |pages=1093–8 |date=Jul 2003 |pmid=14499289 |doi=10.1016/S0196-9781(03)00176-1 |name-list-style=vanc|author2=Ruscetti FW |author3=Pert CB |display-authors=3 |last4=Tractenberg |first4=RE |last5=Leoung |first5=G |last6=Strang |first6=S |last7=Ruff |first7=MR|s2cid=40797488 }} Elimination of viral reservoirs, such as the persistently infected monocytes or brain microglia, is an important treatment goal.{{cite journal |vauthors=Crowe SM, Sonza S |title=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 |journal=J. Leukoc. Biol. |volume=68 |issue=3 |pages=345–50 |date=Sep 2000 |doi=10.1189/jlb.68.3.345 |pmid=10985250 |url=http://www.jleukbio.org/cgi/pmidlookup?view=long&pmid=10985250|url-access=subscription }}

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.{{Cite journal|url=https://pubmed.ncbi.nlm.nih.gov/22033364/|pmid = 22033364|year = 2012|author1 = Padi SSV|last2 = Shi|first2 = X. Q.|last3 = Zhao|first3 = Y. Q.|last4 = Ruff|first4 = M. R.|last5 = Baichoo|first5 = N.|last6 = Pert|first6 = C. B.|last7 = Zhang|first7 = J.|title = Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation|journal = Pain|volume = 153|issue = 1|pages = 95–106|doi = 10.1016/j.pain.2011.09.022|s2cid = 28310179}} RAP-103 also blocks CCR8,{{Cite journal|url=https://pubmed.ncbi.nlm.nih.gov/29248693/|pmid = 29248693|year = 2018|last1 = Noda|first1 = M.|last2 = Tomonaga|first2 = D.|last3 = Kitazono|first3 = K.|last4 = Yoshioka|first4 = Y.|last5 = Liu|first5 = J.|last6 = Rousseau|first6 = J. P.|last7 = Kinkead|first7 = R.|last8 = Ruff|first8 = M. R.|last9 = Pert|first9 = C. B.|title = Neuropathic pain inhibitor, RAP-103, is a potent inhibitor of microglial CCL1/CCR8|journal = Neurochemistry International|volume = 119|pages = 184–189|doi = 10.1016/j.neuint.2017.12.005|s2cid = 23454214}} which may be important in neuropathic pain.{{Cite journal|url=https://pubmed.ncbi.nlm.nih.gov/28961489/|pmid = 28961489|year = 2017|last1 = Zychowska|first1 = M.|last2 = Rojewska|first2 = E.|last3 = Piotrowska|first3 = A.|last4 = Kreiner|first4 = G.|last5 = Nalepa|first5 = I.|last6 = Mika|first6 = J.|title = Spinal CCL1/CCR8 signaling interplay as a potential therapeutic target - Evidence from a mouse diabetic neuropathy model|journal = International Immunopharmacology|volume = 52|pages = 261–271|doi = 10.1016/j.intimp.2017.09.021|s2cid = 25901496}} Inhibitors of CCR5, including DAPTA,{{Cite journal|url=https://pubmed.ncbi.nlm.nih.gov/8461978/|pmid = 8461978|year = 1993|last1 = Hill|first1 = J. M.|last2 = Mervis|first2 = R. F.|last3 = Avidor|first3 = R.|last4 = Moody|first4 = T. W.|last5 = Brenneman|first5 = D. E.|title = HIV envelope protein-induced neuronal damage and retardation of behavioral development in rat neonates|journal = Brain Research|volume = 603|issue = 2|pages = 222–233|doi = 10.1016/0006-8993(93)91241-j|s2cid = 29222082}}{{Cite journal|pmid = 8844774|year = 1996|last1 = Socci|first1 = D. J.|last2 = Pert|first2 = C. B.|last3 = Ruff|first3 = M. R.|last4 = Arendash|first4 = G. W.|title = Peptide T prevents NBM lesion-induced cortical atrophy in aged rats|journal = Peptides|volume = 17|issue = 5|pages = 831–837|doi = 10.1016/0196-9781(96)00106-4|s2cid = 28570986|doi-access = free}} prevent and reverse neurodegeneration and are therapeutic targets in stroke/brain injury{{Cite journal|pmid = 30794775|year = 2019|last1 = Joy|first1 = M. T.|last2 = Ben Assayag|first2 = E.|last3 = Shabashov-Stone|first3 = D.|last4 = Liraz-Zaltsman|first4 = S.|last5 = Mazzitelli|first5 = J.|last6 = Arenas|first6 = M.|last7 = Abduljawad|first7 = N.|last8 = Kliper|first8 = E.|last9 = Korczyn|first9 = A. D.|last10 = Thareja|first10 = N. S.|last11 = Kesner|first11 = E. L.|last12 = Zhou|first12 = M.|last13 = Huang|first13 = S.|last14 = Silva|first14 = T. K.|last15 = Katz|first15 = N.|last16 = Bornstein|first16 = N. M.|last17 = Silva|first17 = A. J.|last18 = Shohami|first18 = E.|last19 = Carmichael|first19 = S. T.|title = CCR5 is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury|journal = Cell|volume = 176|issue = 5|pages = 1143–1157.e13|doi = 10.1016/j.cell.2019.01.044|pmc = 7259116}} and dementia, such as in Parkinsons Disease.{{Cite journal|pmid = 31043478|year = 2019|last1 = Mondal|first1 = S.|last2 = Rangasamy|first2 = S. B.|last3 = Roy|first3 = A.|last4 = Dasarathy|first4 = S.|last5 = Kordower|first5 = J. H.|last6 = Pahan|first6 = K.|title = 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 = Journal of Immunology|volume = 202|issue = 12|pages = 3412–3422|doi = 10.4049/jimmunol.1800587|pmc = 6824976}}