Rationally designed peptidomimetic modulators of a? toxicity in Alzheimer's disease.

ABSTRACT: Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the ?-amyloid (A?) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of A? aggregation designed based on the KLVFF (P1) sequence that is known to bind A? aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of A? aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing A? toxicity. P4 and P5 could rescue yeast cells from A? toxicity and A? aggregates were cleared by the process of autophagy.

SUBMITTER: Rajasekhar K 

PROVIDER: S-EPMC4311240 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature