Molecular design and synthesis of novel peptides from amphibians skin acting as inhibitors of cholinesterase enzymes.
Cholinesterases are a family of enzymes that catalyze the hydrolysis of neurotransmitter acetylcholine. There are two types of cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which differ in their distribution in the body. Currently, 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 peptide 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 dynamics simulations on BChE. This is the first report about amphibian peptides and the second one of natural peptides with ChE inhibitory activity. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Departamento de Química Orgánica, Facultad de Bioquímica y Cs. Biológicas (FBCB), Universidad Nacional del Litoral (UNL), Ciudad Universitaria, 3000, Santa Fe, Argentina.
Alvaro
A
Siano
Facultad de Química, Bioquímica y Farmacia, Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO-SL. CONICET), Universidad Nacional de San Luis, Chacabuco 915, 5700, San Luis, Argentina.
Francisco F
FF
Garibotto
Facultad de Química, Bioquímica y Farmacia, Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO-SL. CONICET), Universidad Nacional de San Luis, Chacabuco 915, 5700, San Luis, Argentina.
Sebastian A
SA
Andujar
Facultad de Química, Bioquímica y Farmacia, Instituto de Matemática Aplicada San Luis, Universidad Nacional de San Luis (UNSL, CONICET), Ejército de Los Andes 950, 5700, San Luis, Argentina.
Hector A
HA
Baldoni
Departamento de Química Orgánica, Facultad de Bioquímica y Cs. Biológicas (FBCB), Universidad Nacional del Litoral (UNL), Ciudad Universitaria, 3000, Santa Fe, Argentina.
Georgina G
GG
Tonarelli
Facultad de Química, Bioquímica y Farmacia, Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO-SL. CONICET), Universidad Nacional de San Luis, Chacabuco 915, 5700, San Luis, Argentina.
Ricardo D
RD
Enriz
D000110:Acetylcholinesterase / Q000737:chemistry*; D000595:Amino Acid Sequence; D029845:Amphibian Proteins / Q000737:chemistry*; D000818:Animals; D001001:Anura; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques / Q000379:methods; D013329:Structure-Activity Relationship
D029845:Amphibian Proteins; D002800:Cholinesterase Inhibitors; D010455:Peptides; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
acetylcholinesterase; butyrylcholinesterase; docking; molecular dynamics; peptide