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A Chemical Strategy to Improve Bioavailability of Glypromate Peptide-Conjugates
* 1, 2 , 1 , 3 , 2, 4 , 5 , 1
1  LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
2  UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
3  LAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Porto, Portugal.
4  Associate Laboratory i4HB – Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal.
5  Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain.
Academic Editor: Alfredo Berzal-Herranz (registering DOI)

Alzheimer's (AD) and Parkinson's (PD) diseases are the main neurodegenerative disorders of the central nervous system, affecting millions of people worldwide. The absence of effective and curative therapies to slow down the progression of neurodegenerative processes constitutes a serious medical concern. In this sense, the development of new neuroprotective therapies becomes imperative. Glypromate is an endogenous neuropeptide with the sequence of Gly-Pro-Glu which displays evidence of neuroprotective activity in many in vitro models of AD and PD. Despite its neuroprotective potential use in the clinical, this neuropeptide exhibits low intestinal absorption, liability towards enzymatic proteolysis, and reduced blood-brain barrier permeability. In fact, clinical trials led by Neuren Pharmaceuticals with Glypromate failed in phase III. The use of constrained proline mimetics and capping strategies have been employed in the assembly of bioactive Glypromate analogues to improve lipophilicity and enhance enzymatic stability. Considering this rationale, the NeuroPro project aims at the design, synthesis, and biological evaluation of novel constrained Glypromate analogues. NeuroPro also explores the chemical conjugation of these constrained peptidomimetics with relevant active pharmaceutical ingredients (APIs) used in AD and PD therapy. This approach is expected to deliver new neuroprotective hits with higher metabolic resistance while exploring synergism between Glypromate analogues and APIs. In this work, the synthesis of 52 new Glypromate conjugates with Amantadine, Memantine, and Aminoindane is disclosed. These peptide-conjugates are currently undergoing biological evaluation to assess their cytotoxicity in human differentiated SH-SY5Y cells. The conjugates with the lowest cytotoxicity will be selected to proceed with neuroprotection studies.

Keywords: Active Pharmaceutical Ingredients; Neurodegenerative Diseases; Peptide-conjugates