Molecular design and synthesis of novel peptides from amphibians skin acting as inhibitors of cholinesterase enzymes

SIANO ALVARO; GARIBOTTO, FRANCISCO; ANDUJAR SEBASTIAN; HÉCTOR ARMANDO BALDONI; TONARELLI GEORGINA; RICARDO D. ENRIZ

JOURNAL OF PEPTIDE SCIENCE : AN OFFICIAL PUBLICATION OF THE EUROPEAN PEPTIDE SOCIETY.

JOHN WILEY & SONS LTD

Lugar: LOndres; Año: 2017

1075-2617

Cholinesterases are a family of enzymes that catalyze the hydrolysis of neurotransmitter acetylcholine. There are two types of cho- linesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which differ in their distribution in the body. Cur- rently, cholinesterase inhibitors (ChEI) represent the treatment of choice for Alzheimer?s disease (AD). In this paper, we report the synthesis and inhibitory effect on both enzymes of four new peptides structurally related to P1-Hp-1971 (amphibian skin pep- tide found in our previous work. Sequence: TKPTLLGLPLGAGPAAGPGKR-NH2). The bioassay data and cytotoxicity test show that some of the compounds possess a significant AChE and BChE inhibition and no toxic effect. The present work demonstrates that diminution of the size of the original peptide could potentially result in new compounds with significant cholinesterase inhibition activity, although it appears that there is an optimal size for the sequence. We also conducted an exhaustive molecular modeling study to better understand the mechanism of action of these compounds by combining docking techniques with molecular dy- namics simulations on BChE. This is the first report about amphibian peptides and the second one of natural peptides with ChE inhibitory activity.