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
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.