Chemistry:Cyclic glycine-proline

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Short description: Small neuroactive peptide

Cyclic glycine-proline
Clinical data
Other namesCycloprolylglycine; Cyclo-Gly-Pro; Cyclo-Pro-Gly; CGP; Cyclo-GP; Biocovax; Biomedivir; Dexaneurosone; NA-831; NA-81; Nanomedivir; Neurosivir; Traneurocine; (S)-Hexahydropyrrolo[1,2-a]pyrazine-1,4-dione
Drug classNeuroprotective; Neurogenesis stimulant; Cognitive enhancer
Pharmacokinetic data
Elimination half-life7 hours[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC7H10N2O2
Molar mass154.169 g·mol−1
3D model (JSmol)

Cyclic glycine-proline (cGP) is a small neuroactive peptide that belongs to a group of bioactive 2,5-diketopiperazines (2,5-DKPs) and is also known as cyclo-glycine-proline. cGP is a neutral, stable naturally occurring compound and is endogenous to the human body; found in human plasma, breast milk and cerebrospinal fluid. DKPs are bioactive compounds often found in foods. Cyclic dipeptides such as 2,5 DKPs are formed by the cyclisation of two amino acids of linear peptides produced in heated or fermented foods.[2] The bioactivity of cGP is a property of functional foods and presents in several matrices of foods including blackcurrants.[3]

cGP is metabolite of hormone insulin-like growth factor-1 (IGF-1). It has a cyclic structure, lipophilic nature, and is enzymatically stable which makes its a more favorable candidate for manipulating the binding-release process between IGF-1 and its binding protein thereby, normalizing IGF-1 function.[4]

Under the trade name Traneurocin (developmental code name NA-831), it is being developed as a racetam-like drug for the treatment of COVID-19, Alzheimer's disease, fragile X syndrome, Rett syndrome, major depressive disorder, and other neurological disorders.[5][6][7] In the case of COVID-19, it is specifically being developed for treatment of COVID-19-induced neuropathy.[8]

Endogenous synthesis

Insulin-like growth factor-1 (IGF-1) is a hormone that is structurally very similar to insulin and mediates the effects of growth hormone (GH) thus affecting metabolism, regeneration, and overall development.[9] The GH-IGF-1 signaling pathway is crucial in the process of vascular remodeling and angiogenesis, i.e., the process of building new blood vessels and thus, helps in maintaining blood circulation in the body.[10][11] In the brain, IGF-1 is abundant in various cells and regions and research over the years, suggest an imperative role of IGF-1 activity in neurodevelopment making it critical in learning and memory.[12]

The IGF-1 family comprises

  • IGF-1,
  • IGF receptors (IGF-1R) and
  • IGF binding proteins (IGFBP).

The therapeutic applications of IGF-1 are limited due to its poor central uptake and potential side-effects. IGF-1 that is not bound to its binding protein bears a very short half-life and is cleaved by enzymes to form the tripeptide glycine-proline-glutamate (GPE). However, the enzymatic instability of GPE, with a plasma half-life of less than 4 minutes, is further cleaved to produce the final product, cyclic-Glycine-Proline (cGP).[4][12][13]

Biological Role of cGP

The hepatic production of IGF-1 is controlled by the growth hormone (GH)-IGF-1 axis.[14] The majority of circulating IGF-1 is not bioavailable because of its affinity and binding to IGF-binding protein (IGFBP), mainly IGFBP3. IGF-1 bioactivity is therefore, tightly regulated through reversible binding with IGFBP3.[15] It is this binding-release process that determines the amount of bioavailable IGF-1 in circulation. IGF-1 that is not bound, is cleaved into an N-terminal tripeptide, Glycine-Proline-Glutamate (GPE) and Des-N-IGF-1.[16] and GPE metabolizes to result in cyclic glycine proline (cGP).[4][17]

Unbound IGF-1, cleaved at the N-terminal, can be metabolized through a series of downstream enzymatic reactions to cGP. The N-terminal is the binding site of IGF-1 which allows cGP to retain the same binding affinity to IGFBP-3 and thus, regulates the bioavailability of IGF-1 through competitive binding with IGFBP3. An increase in cGP, would increase competitive advantage and thus, increase the amount of circulating and therefore, bioavailable IGF-1.[18][19][20]

Research shows that cGP can normalize IGF-1 function under pathophysiological conditions of increased or diminished IGF-1 bioactivity.[20]

In vitro studies show that cGP promoted the activity of IGF-1 when insufficient and inhibited the activity of IGF-1 when in excess.[20]

Pharmacology

Pharmacodynamics

The mechanism of action of traneurocin is either unknown or undisclosed.[21][22] However, it has been described as acting as a positive allosteric modulator of the AMPA receptor and has been found to increase brain-derived neurotrophic factor (BDNF) levels.[5][23][7][24] It has also been found to act as a positive allosteric modulator of the GABAA receptor.[25] The drug is described as having neuroprotective, neurogenesis-stimulating, and pro-cognitive or nootropic effects.[26][27][8][1][7] It has also been reported to have antihypoxic and anxiolytic properties.[28][7]

Pharmacokinetics

It is known to be an endogenous compound present at micromolar concentrations in the rat brain and readily crosses the blood–brain barrier.[1][7]

Chemistry

Chemically, traneurocin is a synthetic cyclized dipeptide composed of the amino acids glycine and proline.[6][29][30]

Potential uses

Biologically, cGP is most strongly associated with cognitive benefits, however it also has a role in other biological functions, as outlined below.[31]

Cognition

Vascular health is critical in maintaining cognitive function.[11] IGF-1 plays an essential role in vascular remodelling of the brain and supports cognitive retention.[32] Metabolic IGF-1 levels tend to reduce with age and this reduction appears to be a major contributor to cognitive impairment in older populations.[33][34]

Low or deficient IGF-1 levels can be normalized by cGP, restoring its vascular function.[20] Studies evaluating cGP, IGF-1 and IGFBP3 levels suggest that cGP concentration and cGP/IGF-1 molar ratio were positively associated suggesting that older people with higher plasma cGP concentration (and cGP/IGF-1 molar ratio) have better memory/cognitive retention.[19]

Hypertension

IGF-1 plays a critical role in energy metabolism with deficient IGF-1 levels being implicated in obesity and hypertension.[35]

Stroke

The role of IGF-1 in supporting recovery from stroke, which is a condition of vascular origin, is reported.[36][37] A study in 34 stroke patients reported that patients with higher plasma concentration of cGP made better recovery within 3 months than those with lower cGP levels. Further, patients with higher cGP levels also showed lesser neurological deficits.[38]

Therapeutic Potential

Excessive IGF-1 activity promotes tumorigenesis[13] while reduced IGF-1 activity is linked with diseases such as Alzheimer's[39] and Parkinson's.[19] cGP normalises the autocrine function of IGF-1 under pathological conditions and when there are low levels of cGP in the human body, IGF-1 regulation is compromised.[20] Therefore, it is reasonable to assume that treatment with exogenous cGP could assist with improving IGF-1 implicated health benefits.[4]

Clinical trials

As of September 2024, traneurocin is in phase 3 clinical trials for COVID-19, phase 2 clinical trials for Alzheimer's disease,[40] fragile X syndrome, and Rett syndrome, and phase 1 clinical trials for major depressive disorder.[5] No development has been reported for treatment of other neurological disorders.[5] Traneurocin was first developed, under the name cycloprolylglycine (CPG), in Russia in 1991 as a drug related structurally and pharmacologically to piracetam.[28][7][41] Cycloprolylglycine is also related to and known to be the major metabolite of omberacetam (Noopept).[28]

Another drug, vineurocin (NA-704), is also being developed for treatment of Alzheimer's disease.[42][43] This drug is described as a recombinant growth hormone with neuroprotective and neurogenic effects.[44]

See also

References

  1. ↑ 1.0 1.1 1.2 "P4-202: NA-831 as a Regenerative Therapeutic for Alzheimer's Disease: A Phase 1 Safety, Tolerability and Pharmacokinetics Study". Alzheimer's & Dementia (Wiley) 14 (7S_Part_29). 2018. doi:10.1016/j.jalz.2018.07.023. ISSN 1552-5260. 
  2. ↑ "Investigation of the formation mechanism of proline-containing cyclic dipeptide from the linear peptide". Bioscience, Biotechnology, and Biochemistry 83 (12): 2355–2363. December 2019. doi:10.1080/09168451.2019.1659718. PMID 31462170. 
  3. ↑ "Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson Patients: Potential Treatment to Improve Insulin-Like Growth Factor-1 Function". Nutrients 10 (6): 714. June 2018. doi:10.3390/nu10060714. PMID 29865234. 
  4. ↑ 4.0 4.1 4.2 4.3 Tran LH, "Neuroprotection and neurogenesis by administering cyclic prolyl glycine", US patent 7232798, issued 19 June 2007
  5. ↑ 5.0 5.1 5.2 5.3 "Traneurocin". AdisInsight. Springer Nature Switzerland AG. 25 September 2024. https://adisinsight.springer.com/drugs/800051889. 
  6. ↑ 6.0 6.1 "Delving into the Latest Updates on Traneurocin with Synapse". 19 September 2024. https://synapse.patsnap.com/drug/c500c569063d4c70af222dab403c0593. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Neuropeptide cycloprolylglycine is an endogenous positive modulator of AMPA receptors". Doklady. Biochemistry and Biophysics 471 (1): 387–389. November 2016. doi:10.1134/S160767291606003X. PMID 28058675. 
  8. ↑ 8.0 8.1 "Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval". Journal of Korean Medical Science 39 (14). April 2024. doi:10.3346/jkms.2024.39.e134. PMID 38622939. 
  9. ↑ "Insulin-like growth factor 1 (IGF-1): a growth hormone". Molecular Pathology 54 (5): 311–316. October 2001. doi:10.1136/mp.54.5.311. PMID 11577173. 
  10. ↑ "IGF-1 promotes angiogenesis in endothelial cells/adipose-derived stem cells co-culture system with activation of PI3K/Akt signal pathway". Cell Proliferation 50 (6). December 2017. doi:10.1111/cpr.12390. PMID 28960620. 
  11. ↑ 12.0 12.1 "The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders". Expert Opinion on Therapeutic Targets 19 (6): 785–793. June 2015. doi:10.1517/14728222.2015.1010514. PMID 25652713. 
  12. ↑ 13.0 13.1 "Is there a role for IGF-1 in the development of second primary cancers?". Cancer Medicine 5 (11): 3353–3367. November 2016. doi:10.1002/cam4.871. PMID 27734632. 
  13. ↑ "Neurotrophic and Neuroregenerative Effects of GH/IGF1". International Journal of Molecular Sciences 18 (11): 2441. November 2017. doi:10.3390/ijms18112441. PMID 29149058. 
  14. ↑ "Insulin-like growth factors and their binding proteins". Physiological Reviews 70 (3): 591–614. July 1990. doi:10.1152/physrev.1990.70.3.591. PMID 1694588. 
  15. ↑ "Generation of des-(1-3) insulin-like growth factor-I in serum by an acid protease". Endocrinology 135 (6): 2432–2439. December 1994. doi:10.1210/endo.135.6.7988428. PMID 7988428. 
  16. ↑ "Glyproline peptide family: review on bioactivity and possible origins". Pathophysiology 8 (4): 229–234. August 2002. doi:10.1016/S0928-4680(02)00018-4. PMID 12100966. 
  17. ↑ "Plasma cyclic glycine proline/IGF-1 ratio predicts clinical outcome and recovery in stroke patients". Annals of Clinical and Translational Neurology 6 (4): 669–677. April 2019. doi:10.1002/acn3.743. PMID 31019991. 
  18. ↑ 19.0 19.1 19.2 "Changes of plasma cGP/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease". Alzheimer's & Dementia 12 (1). January 2020. doi:10.1002/dad2.12025. PMID 32671179. 
  19. ↑ 20.0 20.1 20.2 20.3 20.4 "Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1". Scientific Reports 4 (1). March 2014. doi:10.1038/srep04388. PMID 24633053. Bibcode: 2014NatSR...4.4388G. 
  20. ↑ "Old Drugs with New Tricks: Paradigm in Drug Development Pipeline for Alzheimer's Disease". Central Nervous System Agents in Medicinal Chemistry 20 (3): 157–176. 2020. doi:10.2174/1871524920666201021164805. PMID 33087034. 
  21. ↑ "Alzheimer's disease drug development pipeline: 2019". Alzheimer's & Dementia (Wiley) 5 (1): 272–293. 2019. doi:10.1016/j.trci.2019.05.008. PMID 31334330. 
  22. ↑ "NA-831". 28 November 2023. https://www.alzforum.org/therapeutics/na-831. 
  23. ↑ "Neuropeptide cycloprolylglycine increases the levels of brain-derived neurotrophic factor in neuronal cells". Doklady. Biochemistry and Biophysics 469 (1): 273–276. July 2016. doi:10.1134/S1607672916040104. PMID 27599510. 
  24. ↑ "Effect of Endogenous Neuropeptide Cycloprolylglycine on GABAA Receptors in Cerebellar Purkinje Cells". Bulletin of Experimental Biology and Medicine 167 (1): 39–42. May 2019. doi:10.1007/s10517-019-04455-7. PMID 31177457. 
  25. ↑ "Antiretrovirals for Prophylaxis Against COVID-19: A Comprehensive Literature Review". Journal of Clinical Pharmacology 61 (5): 581–590. May 2021. doi:10.1002/jcph.1788. PMID 33217030. 
  26. ↑ "Pulmonary drug delivery: an effective and convenient delivery route to combat COVID-19". Drug Delivery and Translational Research 13 (3): 705–715. March 2023. doi:10.1007/s13346-022-01251-1. PMID 36260223. 
  27. ↑ 28.0 28.1 28.2 "Theoretical grounds and technologies for dipeptide drug development". Russian Chemical Bulletin (Springer Science and Business Media LLC) 64 (9): 2012–2021. 2015. doi:10.1007/s11172-015-1112-2. ISSN 1066-5285. 
  28. ↑ "Cyclo(prolylglycyl): Uses, Interactions, Mechanism of Action". 13 June 2005. https://go.drugbank.com/drugs/DB04541. 
  29. ↑ "(S)-Hexahydropyrrolo[1,2-apyrazine-1,4-dione"]. https://pubchem.ncbi.nlm.nih.gov/compound/126154. 
  30. ↑ "Exploring Sources, Biological Functions, and Potential Applications of the Ubiquitous Marine Cyclic Dipeptide: A Concise Review of Cyclic Glycine-Proline". Marine Drugs 22 (6): 271. June 2024. doi:10.3390/md22060271. PMID 38921582. 
  31. ↑ "Insulin-like growth factor I is required for vessel remodeling in the adult brain". Proceedings of the National Academy of Sciences of the United States of America 101 (26): 9833–9838. June 2004. doi:10.1073/pnas.0400337101. PMID 15210967. Bibcode: 2004PNAS..101.9833L. 
  32. ↑ "Midlife plasma insulin-like growth factor I and cognitive function in older men". The Journal of Clinical Endocrinology and Metabolism 91 (11): 4306–4312. November 2006. doi:10.1210/jc.2006-1325. PMID 16912125. 
  33. ↑ "Plasma IGF-I levels and cognitive performance in older women". Neurobiology of Aging 28 (1): 135–142. January 2007. doi:10.1016/j.neurobiolaging.2005.10.012. PMID 16337715. 
  34. ↑ "All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies". Blood Reviews 29 (2): 71–80. March 2015. doi:10.1016/j.blre.2014.09.010. PMID 25433571. 
  35. ↑ "Vascular mechanisms in the pathogenesis of stroke". Current Hypertension Reports 13 (3): 200–207. June 2011. doi:10.1007/s11906-011-0195-x. PMID 21331606. 
  36. ↑ "Insulin-like growth factor-1 and post-ischemic brain injury". Progress in Neurobiology 70 (6): 443–462. August 2003. doi:10.1016/j.pneurobio.2003.08.002. PMID 14568359. 
  37. ↑ "Plasma cyclic glycine proline/IGF-1 ratio predicts clinical outcome and recovery in stroke patients". Annals of Clinical and Translational Neurology 6 (4): 669–677. April 2019. doi:10.1002/acn3.743. PMID 31019991. 
  38. ↑ "The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer's disease". Psychoneuroendocrinology 127. May 2021. doi:10.1016/j.psyneuen.2021.105191. PMID 33706042. 
  39. ↑ Biomed Industries, Inc. (2020-06-26). A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, and Efficacy of NA-831 in Alzheimer Patients With Mild Cognitive Impairment (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT03538522. 
  40. ↑ "Mechanism of nootropic effect of topological proline-based piracetam analogues.". Khim.-Farm. Zh. 25 (6): 12–16. 1991. https://scholar.google.com/scholar?cluster=3952160753610416095. 
  41. ↑ "Vineurocine". AdisInsight. Springer Nature Switzerland AG. 7 April 2021. https://adisinsight.springer.com/drugs/800051886. 
  42. ↑ "Delving into the Latest Updates on Vineurocin with Synapse". 28 September 2024. https://synapse.patsnap.com/drug/b410f62c2730498c9a2d32bb588a8218. 
  43. ↑ "1st NIF Presenting Companies". 18 September 2017. https://www.sachsforum.com/nif-presenters.html. "2. Our second drug candidate, Vineurocin (NA-704) is a recombinant human growth hormone that modulates the aging process in humans. NA-704 exhibits neuroprotection and neurogenesis, which has been demonstrated as a strong candidate for treatment of Alzheimer's disease and other neurological disorders. The NA-704 Phase 2 will be from June 2018 to May 2019." 



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