Beta-amyloid oligomers are thought to be the most toxic species formed en route to fibril deposition in the Alzheimer’s brain, so sequestration of these low molecular weight structures may have a beneficial effect. Transthyretin, a tetrameric carrier protein that circulates in blood and cerebrospinal fluid, is a natural sequestering agent of beta-amyloid oligomers. A monomeric mutant of transthyretin, mTTR, shows significant promise as a beta-amyloid scavenger that does not disrupt transthyretin’s normal physiological function. However, mTTR is susceptible to proteolysis, and binding of beta-amyloid to mTTR is significantly reduced in the presence of nonspecific proteins and lipids. We proposed that these concerns could be overcome by careful design of a small peptide mimic of the beta-amyloid binding domain contained in strands G and H of mTTR. Linear peptides that mimicked the sequence of the beta-amyloid binding domain on mTTR were only moderately effective at sequestering beta-amyloid. Cyclization improved efficacy, greatly increased stability, and demonstrated less nonspecific interference compared to mTTR. However, the first designed cyclic peptide was not as potent as mTTR. We hypothesized that the lower efficacy was the result of a higher degree of conformational flexibility in the peptide compared to mTTR. Using the ROSETTA software suite as an <i>in silico</i> predictor of cyclic peptide conformation stability and heterogeneity, a screening procedure was developed to investigate putative structural enhancements, including adjustments to secondary structure motifs and stabilization by disulfide linkages. The best candidates from this design approach were synthesized and tested for structure and efficacy compared to mTTR. This approach supports the use of ROSETTA simulations as a screening method to investigate sequence and structure effects on the conformation of cyclic peptides in the search for beta-amyloid-sequestering peptides. Such peptides can overcome the protease stability and nonspecific interference issues of the protein while retaining the therapeutic efficacy.<br/>

ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides

2019 Spring National Meeting

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