Cyclic glycine-proline

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Cyclic glycine-proline
Traneurocin.svg
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 class Neuroprotective; Neurogenesis stimulant; Cognitive enhancer
Pharmacokinetic data
Elimination half-life 7 hours [1]
Identifiers
  • (8aS)-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C7H10N2O2
Molar mass 154.169 g·mol−1
3D model (JSmol)
  • C1C[C@H]2C(=O)NCC(=O)N2C1
  • InChI=1S/C7H10N2O2/c10-6-4-8-7(11)5-2-1-3-9(5)6/h5H,1-4H2,(H,8,11)/t5-/m0/s1
  • Key:OWOHLURDBZHNGG-YFKPBYRVSA-N

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]

Contents

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

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

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  2. ↑ Otsuka Y, Arita H, Sakaji M, Yamamoto K, Kashiwagi T, Shimamura T, et al. (December 2019). "Investigation of the formation mechanism of proline-containing cyclic dipeptide from the linear peptide". Bioscience, Biotechnology, and Biochemistry. 83 (12): 2355–2363. doi: 10.1080/09168451.2019.1659718 . PMID   31462170. S2CID   201663846.
  3. ↑ Fan D, Alamri Y, Liu K, MacAskill M, Harris P, Brimble M, et al. (June 2018). "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. doi: 10.3390/nu10060714 . PMC   6024688 . PMID   29865234.
  4. 1 2 3 4 US 7232798,Tran LH,"Neuroprotection and neurogenesis by administering cyclic prolyl glycine",issued 19 June 2007, assigned to NeuroBioMed Corp.
  5. 1 2 3 4 "Traneurocin". AdisInsight. Springer Nature Switzerland AG. 25 September 2024. Retrieved 19 October 2024.
  6. 1 2 "Delving into the Latest Updates on Traneurocin with Synapse". Synapse. 19 September 2024. Retrieved 19 October 2024.
  7. 1 2 3 4 5 6 Gudasheva TA, Grigoriev VV, Koliasnikova KN, Zamoyski VL, Seredenin SB (November 2016). "Neuropeptide cycloprolylglycine is an endogenous positive modulator of AMPA receptors". Doklady. Biochemistry and Biophysics. 471 (1): 387–389. doi:10.1134/S160767291606003X. PMID   28058675.
  8. 1 2 Choi HS, Choi AY, Kopp JB, Winkler CA, Cho SK (April 2024). "Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval". Journal of Korean Medical Science. 39 (14) e134. doi:10.3346/jkms.2024.39.e134. PMC   11018982 . PMID   38622939.
  9. ↑ Laron Z (October 2001). "Insulin-like growth factor 1 (IGF-1): a growth hormone". Molecular Pathology. 54 (5): 311–316. doi:10.1136/mp.54.5.311. PMC   1187088 . PMID   11577173.
  10. ↑ Lin S, Zhang Q, Shao X, Zhang T, Xue C, Shi S, et al. (December 2017). "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) e12390. doi:10.1111/cpr.12390. PMC   6529130 . PMID   28960620. S2CID   8857741.
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  12. 1 2 Shanmugalingam T, Bosco C, Ridley AJ, Van Hemelrijck M (November 2016). "Is there a role for IGF-1 in the development of second primary cancers?". Cancer Medicine. 5 (11): 3353–3367. doi:10.1002/cam4.871. PMC   5119990 . PMID   27734632.
  13. ↑ Bianchi VE, Locatelli V, Rizzi L (November 2017). "Neurotrophic and Neuroregenerative Effects of GH/IGF1". International Journal of Molecular Sciences. 18 (11): 2441. doi: 10.3390/ijms18112441 . PMC   5713408 . PMID   29149058.
  14. ↑ Sara VR, Hall K (July 1990). "Insulin-like growth factors and their binding proteins". Physiological Reviews. 70 (3): 591–614. doi:10.1152/physrev.1990.70.3.591. PMID   1694588.
  15. ↑ Yamamoto H, Murphy LJ (December 1994). "Generation of des-(1-3) insulin-like growth factor-I in serum by an acid protease". Endocrinology. 135 (6): 2432–2439. doi:10.1210/endo.135.6.7988428. PMID   7988428.
  16. ↑ Samonina G, Ashmarin I, Lyapina L (August 2002). "Glyproline peptide family: review on bioactivity and possible origins". Pathophysiology. 8 (4): 229–234. doi: 10.1016/S0928-4680(02)00018-4 . PMID   12100966.
  17. ↑ Fan D, Krishnamurthi R, Harris P, Barber PA, Guan J (April 2019). "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. doi:10.1002/acn3.743. PMC   6469247 . PMID   31019991. S2CID   104430959.
  18. 1 2 3 Fan D, Pitcher T, Dalrymple-Alford J, MacAskill M, Anderson T, Guan J (January 2020). "Changes of plasma cGP/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease". Alzheimer's & Dementia. 12 (1): e12025. doi:10.1002/dad2.12025. PMC   7346731 . PMID   32671179.
  19. 1 2 3 4 5 Guan J, Gluckman P, Yang P, Krissansen G, Sun X, Zhou Y, et al. (March 2014). "Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1". Scientific Reports. 4 (1) 4388. Bibcode:2014NatSR...4.4388G. doi:10.1038/srep04388. PMC   3955921 . PMID   24633053.
  20. ↑ Dalvi T, Dewangan B, Das R, Rani J, Shinde SD, Vhora N, et al. (2020). "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. doi:10.2174/1871524920666201021164805. PMID   33087034.
  21. ↑ Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K (2019). "Alzheimer's disease drug development pipeline: 2019". Alzheimer's & Dementia. 5 (1). Wiley: 272–293. doi: 10.1016/j.trci.2019.05.008 . PMC   6617248 . PMID   31334330.
  22. ↑ "NA-831". ALZFORUM. 28 November 2023. Retrieved 19 October 2024.
  23. ↑ Gudasheva TA, Koliasnikova KN, Antipova TA, Seredenin SB (July 2016). "Neuropeptide cycloprolylglycine increases the levels of brain-derived neurotrophic factor in neuronal cells". Doklady. Biochemistry and Biophysics. 469 (1): 273–276. doi:10.1134/S1607672916040104. PMID   27599510.
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  26. ↑ Alipour S, Mahmoudi L, Ahmadi F (March 2023). "Pulmonary drug delivery: an effective and convenient delivery route to combat COVID-19". Drug Delivery and Translational Research. 13 (3): 705–715. doi:10.1007/s13346-022-01251-1. PMC   9580423 . PMID   36260223.
  27. 1 2 3 Gudasheva TA (2015). "Theoretical grounds and technologies for dipeptide drug development". Russian Chemical Bulletin. 64 (9). Springer Science and Business Media LLC: 2012–2021. doi:10.1007/s11172-015-1112-2. ISSN   1066-5285.
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  29. ↑ "(S)-Hexahydropyrrolo[1,2-a]pyrazine-1,4-dione". PubChem. Retrieved 19 October 2024.
  30. ↑ Hu L, Lin J, Qin F, Xu L, Luo L (June 2024). "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. doi: 10.3390/md22060271 . PMC   11205142 . PMID   38921582.
  31. ↑ Lopez-Lopez C, LeRoith D, Torres-Aleman I (June 2004). "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. Bibcode:2004PNAS..101.9833L. doi: 10.1073/pnas.0400337101 . PMC   470760 . PMID   15210967.
  32. ↑ Okereke OI, Kang JH, Ma J, Gaziano JM, Grodstein F (November 2006). "Midlife plasma insulin-like growth factor I and cognitive function in older men". The Journal of Clinical Endocrinology and Metabolism. 91 (11): 4306–4312. doi: 10.1210/jc.2006-1325 . PMID   16912125.
  33. ↑ Okereke O, Kang JH, Ma J, Hankinson SE, Pollak MN, Grodstein F (January 2007). "Plasma IGF-I levels and cognitive performance in older women". Neurobiology of Aging. 28 (1): 135–142. doi:10.1016/j.neurobiolaging.2005.10.012. PMID   16337715. S2CID   44509810.
  34. ↑ Karmali R, Dalovisio A, Borgia JA, Venugopal P, Kim BW, Grant-Szymanski K, et al. (March 2015). "All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies". Blood Reviews. 29 (2): 71–80. doi:10.1016/j.blre.2014.09.010. PMID   25433571.
  35. ↑ Sierra C, Coca A, Schiffrin EL (June 2011). "Vascular mechanisms in the pathogenesis of stroke". Current Hypertension Reports. 13 (3): 200–207. doi:10.1007/s11906-011-0195-x. PMID   21331606. S2CID   13442699.
  36. ↑ Guan J, Bennet L, Gluckman PD, Gunn AJ (August 2003). "Insulin-like growth factor-1 and post-ischemic brain injury". Progress in Neurobiology. 70 (6): 443–462. doi:10.1016/j.pneurobio.2003.08.002. PMID   14568359. S2CID   12719687.
  37. ↑ Fan D, Krishnamurthi R, Harris P, Barber PA, Guan J (April 2019). "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. doi:10.1002/acn3.743. PMC   6469247 . PMID   31019991. S2CID   104430959.
  38. ↑ Kang D, Waldvogel HJ, Wang A, Fan D, Faull RL, Curtis MA, et al. (May 2021). "The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer's disease". Psychoneuroendocrinology. 127 105191. doi:10.1016/j.psyneuen.2021.105191. PMID   33706042. S2CID   232116896.
  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.
  40. ↑ Gudasheva TA, Vasilevich NI, Zolotov NN, Lezina VP, Rozenberg SG, Kravchenko EV, et al. (1991). "Mechanism of nootropic effect of topological proline-based piracetam analogues". Khim.-Farm. Zh. 25 (6): 12–16.
  41. ↑ "Vineurocine". AdisInsight. Springer Nature Switzerland AG. 7 April 2021. Retrieved 19 October 2024.
  42. ↑ "Delving into the Latest Updates on Vineurocin with Synapse". Synapse. 28 September 2024. Retrieved 19 October 2024.
  43. ↑ "1st NIF Presenting Companies". SachsForum. 18 September 2017. Retrieved 19 October 2024. 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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