Cyclic Peptide Inhibitors that Interfere with Amyloidogenic Signal Transduction
Synthetic heterocyclic peptides that were reported to exhibit anti-amyloidogenic activity without interacting directly with amyloids include several cyclic peptide inhibitors that interfere with amyloidogenic pathways with partially understood mechanisms. For example, some of the heterocyclic peptides were designed to target protease enzymes. Others act on various receptors and cellular pathways that have yet to be associated directly with amyloid pathology.
Cyclic Peptides Selected by In Vivo Screening
Although the mechanism of action of these cyclic peptides is not yet understood, the method for their selection has important value in anti-amyloidogenic research. Libraries of head-to-tail cyclic peptides were generated in vivo to enable chemical genetic selection [107]. Using an in vivo yeast model for Parkinson’s disease (PD) and other synucleinopathies, rapid phenotypic selection identified peptides that reduced specifically a-syn toxicity [108]. From an original pool of 5 million cyclic octapeptides, two cyclic peptides (CPWCSTRV and CALCDPWW, Fig. 8a, b) were isolated and their activity was validated in additional filtering assays. Studies of SAR by point mutagenesis revealed that the biological activity of both cyclic peptides requires the presence of Cys in the first position of a common CXФX motif, in which X is any residue and Ф is a hydrophobic amino acid. The two selected cyclic peptides reduced significantly dopaminergic neuron loss in a nematode synucleinopathy PD model. Immuno-electron and EM results demonstrated that both cyclic peptides permitted the growth and division of the dopaminergic neurons despite the presence of hindered pools of a-syn vesicles that killed control cells. The cyclic peptides were hypothesized to target cell pathways downstream of a-syn-mediated vesicle trafficking defects and to alter likely cellular functions distinct from those linked to a-syn toxicity [108]. In addition to discovering new lead compounds, this study accomplished development of a novel
Fig. 8 Structures of some cyclic peptides that interfere with amyloidogenic signal transduction: (a) CP1R7K, (b) CP2W7K cyclic peptides discovered by screening chemical genetic drug candidates in vivo [108], (c) p-secretase inhibitor NB-544, and (d) macrocycleNB-216 [109, 110]
technology for screening chemical genetic drug candidates in vivo. The method has been utilized in various disease models, including those difficult to address in vitro, and may prove a lower-cost, higher throughput alternative to traditional small molecule screening.
