A Cyclic Peptide Mimic of the ?-Amyloid Binding Domain on Transthyretin.

ABSTRACT: Self-association of ?-amyloid (A?) into oligomers and fibrils is associated with Alzheimer's disease (AD), motivating the search for compounds that bind to and inhibit A? oligomerization and/or neurotoxicity. Peptides are an attractive class of such compounds, with potential advantages over small molecules in affinity and specificity. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to A?. Alternatively, one could design A?-binding peptides based on knowledge of complementary binding proteins. One candidate protein, transthyretin (TTR), binds A?, inhibits aggregation, and reduces its toxicity. Previously, strand G of TTR was identified as part of a specific A? binding domain, and G16, a 16-mer peptide with a sequence that spans strands G and H of TTR, was synthesized and tested. Although both TTR and G16 bound to A?, they differed significantly in their effect on A? aggregation, and G16 was less effective than TTR at protecting neurons from A? toxicity. G16 lacks the ?-strand/loop/?-strand structure of TTR's A? binding domain. To enforce proper residue alignment, we transplanted the G16 sequence onto a ?-hairpin template. Two peptides with 18 and 22 amino acids were synthesized using an orthogonally protected glutamic acid derivative, and an N-to-C cyclization reaction was carried out to further restrict conformational flexibility. The cyclized 22-mer (but not the noncyclized 22-mer nor the 18-mer) strongly suppressed A? aggregation into fibrils, and protected neurons against A? toxicity. The imposition of structural constraints generated a much-improved peptidomimetic of the A? binding epitope on TTR.

SUBMITTER: Cho PY 

PROVIDER: S-EPMC4797071 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature