Design, Synthesis and Enzymatic Inhibition of Novel Unusual Amino Acids as a Transition State Analogue of Amyloid Precur
- PDF / 1,037,035 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 83 Downloads / 139 Views
Design, Synthesis and Enzymatic Inhibition of Novel Unusual Amino Acids as a Transition State Analogue of Amyloid Precursor Protein Peptide Atefe Ghodrati1 · Loghman Firoozpour2 · Saeed Balalaie3 · Faezeh Sadat Hosseini1 · Sorour Ramezanpour3 · Najme Edraki4 · Naser Mohtavinejad5 · Massoud Amanlou1,6 Accepted: 2 January 2020 © Springer Nature B.V. 2020
Abstract β-secretase 1 (BACE1) plays a pivotal role in the pathology of Alzheimer׳s disease via accumulation beta amyloid in the brain. In this context, identifying new scaffolds that block BACE1 is of great importance despite all pharmacokinetic drawbacks that peptide-like structures have. Here, we report a new core structure based on novel unusual amino acids by substituting phenyl amide group in the P1 position and small alkyl groups in the P1′ site that results in the formation of new biological active peptides in micromolar level. Three different scaffolds were designed based on docking studies to efficiently interact with critical Asp32 residue in the active site of BACE1 and incorporated in peptides synthesis by Fmoc solid-phase peptide synthesis (SPPS) methodology to achieve desired compounds in good yield. The inhibitory activity of all synthesized peptides was examined by FRET-based enzymatic assay. The peptide 7 showed the best inhibitory activity with IC50 = 98.14 µM. Results of this investigation revealed that utilizing unusual amino acids as building blocks for the synthesis of peptidomimetics would be an option for the development and optimization of pharmaceutical structures.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10989-020-10015-9) contains supplementary material, which is available to authorized users. * Massoud Amanlou [email protected] 1
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
2
Drug Design, Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
3
Peptide Chemistry Research Center, K. N. Toosi University of Technology, Tehran, Iran
4
Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
5
Department Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
6
Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
13
Vol.:(0123456789)
International Journal of Peptide Research and Therapeutics
Graphic Abstract O O H2N
H N
N H O
O
OH
O
O
HN
O O OH
O
OH
NH
O
N H OH
OH
O
H N
OM00-3
Rational Design
BACE-1 inhibition assessment
O
O
HO NH2
N H
H N O
Docking Methodoloy
H N
O
O
O
N H O
H N O
OH
O NH O
NH
OH O OH
Most Potent (7)
The inhibition of β-secretase 1 (BACE1) is potentially important approach to treatment of Alzheimer disease (AD). Novel series of peptides coupled to the new unusual amino acids scaffold were investigated as BACE1 inhibitors in this study. The d
Data Loading...
