Concise Overview of Glypromate Neuropeptide Research: From Chemistry to Pharmacological Applications in Neurosciences

Abstract

Neurodegenerative diseases of the central nervous system (CNS) pose a serious health concern worldwide, with a particular incidence in developed countries as a result of life expectancy increase and the absence of restorative treatments. Presently, treatments for these neurological conditions are focused on managing the symptoms and/or slowing down their progression. As so, the research on novel neuroprotective drugs is of high interest. Glypromate (glycyl-L-prolyl-L-glutamic acid, also known as GPE), an endogenous small peptide widespread in the brain, holds great promise to tackle neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's, s well as other CNS-related disorders like Rett and Down's syndromes. However, the limited pharmacokinetic properties of Glypromate hinder its clinical application. As such, intense research has been devoted to leveraging the pharmacokinetic profile of this neuropeptide. This review aims to offer an updated perspective on Glypromate research by exploring the vast array of chemical derivatizations of more than 100 analogs described in the literature over the past two decades. The collection and discussion of the most relevant structure−activity relationships will hopefully guide the discovery of new Glypromate-based neuroprotective drugs.

Reduction in Hippocampal Amyloid-β Peptide (Aβ) Content during Glycine-Proline-Glutamate (Gly-Pro-Glu) Co-Administration Is Associated with Changes in Inflammation and Insulin-like Growth Factor (IGF)-I Signaling

“…Hence, the systemic administration of GPE reduces p38MAPK activation [ 40 ] and suppresses the NFκB inflammatory pathway in experimental models of neurodegenerative disease [ 41 ]. The effects of GPE mimic those exerted by IGF-I, increasing Akt activation [ 16 ], although it does not bind to IGF-IR. The activation of the Akt pathway may be favored by the increase in leptin signaling after GPE co-administration, as was reported in other situations [ 42 ], and the increase in serum leptin levels may explain, at least in part, the activation in its signaling and subsequent phosphorylation of IGF-I-related targets.…”

“…Therapies based on the use of different proteins have emerged as a possible strategy due to their high specificity and activity on different biological targets [ 13 ]. Several endogenous peptides have anti-apoptotic and neuroprotective properties in the central nervous system, among which glycine-proline-glutamate (GPE), a natural peptide cleaved from the N-terminus of insulin-like growth factor I (IGF)-I, is a protective agent in brain injury [ 14 ] and has shown neuroprotective capabilities in experimental models of AD [ 15 , 16 ].…”

Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

“…Before the discovery of Trofinetide, GPE demonstrated modulatory effects on neurons and certain CNS enzymes (ChAT, GAD, NOS, and tyrosine hydroxylase) and was claimed to treat neurodegenerative diseases [47][48][49][50]. However, GPE demonstrated some pharmacokinetic-related concerns [69]. These observations led to the discovery of Trofinetide in 2000 by Neuren Pharmaceuticals [51].…”

“…These findings suggest that IGF-1 or its analogs may be promising candidates for further research for RTT treatment. GPE was derivatized to Trofinetide, wherein incorporating the α-methyl group improved the pharmacokinetic profile (half-life, oral bioavailability, and stability against enzymatic degradation) and neuroprotective activity [24,31,41,51,69]. The half-life of Trofinetide is about 1.5 h, necessitating its dosage administration twice a day (about 10 g to 24 g per day, depending on the patient's weight) (Table 4).…”

Reduction in Hippocampal Aβ Content During Gly-Pro-Glu Co-Administration Is Associated with Changes in Inflammation and IGF-I Signaling

“…Therapies based on the use of different proteins have emerged as a possible strategy due to their high specificity and activity on different biological targets [11]. Several endogenous peptides have anti-apoptotic and neuroprotective properties in the central nervous system and among which, glycine-prolineglutamate (GPE) a natural peptide cleaved from the N-terminus of insulin-like growth factor I (IGF)-I, is a protective agent in brain injury [12] and has shown neuroprotective capabilities in experimental models of AD [13,14].…”