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Synthesis and structural investigation of 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing peptide analogue of amyloidogenic AS(6-7) sequence: Inhibition of fibril formation

Abstract

The incorporation of a single beta-amino acid moiety in a highly amyloidogenic peptide sequence resulted in a complete loss of amyloid fibril formation. The Boc-L-Phe-L-Leu-OMe 1 having sequence identity with N-terminal AS (6-7) of the non-immunoglobulin amyloid fibril protein AS responsible for Rheumatoid Arthritis, self-associate to produce fibrils. The D-Phe analogue peptide 2 shows elongated ribbon like morphology. But, 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing analogue peptide 3 exhibits polydisperse microspheres morphology. Moreover, fibrils from peptides 1 and 2 exhibit typical green-gold birefringence on Congo red (CR) binding assay and showing amyloid-like morphological resemblance. But, the 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid modified peptide 3 does not response to this Congo red assay. From X-ray crystallography, the peptide 1 having L-Phe residue adopts extended structure whereas the D-Phe analogue 2 adopts kink-like structure. Both peptides 1 and 2 show twisted anti parallel sheet-like structure at higher order assembly. However, the peptide 3 adopts nine member hydrogen bonded delta-turn like structure in solid state and self-associates to form loop like supramolecular structure through multiple intermolecular hydrogen bonds. The structural analysis presented here may foster new studies for de novo design and therapeutics.

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Publication details

The article was accepted on 18 Apr 2017 and first published on 18 Apr 2017


Article type: Paper
DOI: 10.1039/C7OB00797C
Citation: Org. Biomol. Chem., 2017, Accepted Manuscript
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    Synthesis and structural investigation of 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing peptide analogue of amyloidogenic AS(6-7) sequence: Inhibition of fibril formation

    A. Paikar, M. Debnath, D. Podder, S. Sasmal and D. Haldar, Org. Biomol. Chem., 2017, Accepted Manuscript , DOI: 10.1039/C7OB00797C

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