Design, Synthesis and Enzymatic Inhibition of Novel Unusual Amino Acids as a Transition State Analogue of Amyloid Precursor Protein Peptide

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. 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 design of these peptides was mostly affected by OM00-3. Based on observations, in good agreement between BACE-1 inhibition assessment and docking methodology, peptide 7 was the most potent compound between all and could be the basis of future studies.