Synthesis and biological evaluation of novel analogues of Gly-l-Pro-l-Glu (GPE) as neuroprotective agents. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Marinelli, Lisa; Fornasari, Erika; Di Stefano, Antonio; Turkez, Hasan; Genovese, Salvatore; Epifano, Francesco; Di Biase, Giuseppe; Costantini, Erica; D'Angelo, Chiara; Reale, Marcella; Cacciatore, Ivana
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 2(2019)
• Page Start: 194
• Page End: 198
• Publication Date: 2019-01-15
• Subjects: Alzheimer's disease -- Gly-l-Pro-l-Glu -- Neuroinflammation -- Pseudopeptides; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.11.057
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Neuroprotective pseudopeptides with anti-inflammatory properties. Gly-Pro-Glu pseudopeptides reduced the expression of selected cyto-chemokines. Water-soluble pseudopeptides with improved plasma stability. Abstract: This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1 –3 ) as potential candidates to counteract neuroinflammation processes in Alzheimer's disease. GPE 1 –3 pseudotripeptides are synthetic derivatives of Gly-l -Pro-l -Glu (GPE), the N -terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t1/2 > 4 h) than GPE (t1/2 = 30 min) in human plasma and had good water solubility. The biological results demonstrated thatGPE 1 –3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1β, IL-18, and TNF-α) in Aβ25–35 -, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, bothGPE 1 andGPE 3 reduced the expression levels of all selected cyto-chemokines, even thoughGPE 3 showed the best neuroprotective properties.