A?42-binding peptoids as amyloid aggregation inhibitors and detection ligands.

ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia and currently affects 5.4 million Americans. A number of anti-A? (beta amyloid) therapeutic agents have been developed for AD, but so far all of them failed in clinic. Here we used peptoid chemistry to develop ligands selective for A?42. Peptoids are N-substituted glycine oligomers, a class of peptidomimics. We synthesized an on-bead peptoid library consisting of 38,416 unique peptoids. The generated peptoid library was screened and arrays of A?42-selective peptoid ligands were identified. One of those peptoid ligands, IAM1 (inhibitor of amyloid), and the dimeric form (IAM1)2 were synthesized and evaluated in a variety of biochemical assays. We discovered that IAM1 selectively binds to A?42, while the dimeric derivative (IAM1)2 has a higher affinity for A?42. Furthermore, we demonstrated that IAM1 and (IAM1)2 were able to inhibit the aggregation of A?42 in a concentration-dependent manner, and that (IAM1)2 protected primary hippocampal neurons from the A?-induced toxicity in vitro. These results suggest that IAM1 and (IAM1)2 are specific A?42 ligands with antiaggregation and neuroprotective properties. IAM1, (IAM1)2, and their derivatives hold promise as A?42 detection agents and as lead compounds for the development of AD therapeutic agents.

SUBMITTER: Luo Y 

PROVIDER: S-EPMC3689191 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature