Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease

Abstract

A variety of neurodegenerative disorders, including Alzheimer disease (AD), are associated with neurofibrillary tangles composed of the tau protein, as well as toxic tau oligomers. Inhibitors of pathological tau aggregation, interrupting tau self-assembly, might be useful for the development of therapeutics. Employing mirror image phage display with a large peptide library (over 109 different peptides), we have identified tau fibril binding peptides consisting of d-enantiomeric amino acids. d-enantiomeric peptides are extremely protease stable and not or less immunogenic than l-peptides, and the suitability of d-peptides for in vivo applications have already been demonstrated. Phage display selections were performed using fibrils of the d-enantiomeric hexapeptide VQIVYK, representing residues 306 to 311 of the tau protein, as a target. VQIVYK has been demonstrated to be important for fibril formation of the full lengths protein and forms fibrils by itself. Here, we report on d-enantiomeric peptides, which bind to VQIVYK, tau isoforms like tau3RD (K19) as well as to full lengths tau fibrils, and modulate the aggregation of the respective tau form. The peptides are able to penetrate cells and might be interesting for therapeutic and diagnostic applications in AD research.

Suppressing Tau Aggregation and Toxicity by an Anti-Aggregant Tau Fragment

“…There is thus a need to search for alternative Tau aggregation inhibitors. Indeed, several groups are developing peptides targeting the two hexapeptide motifs of Tau that govern the Tau aggregation process [ 8 , 37 , 38 ]. The advantage to this approach is that the peptides occupy larger and more specific interaction interfaces between Tau molecules than low MW compounds, necessary to inhibit the overall aggregation process.…”

Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies

“…The most studied small inhibitory molecules belong to distinct chemical groups, such as phenotiazines, cyanines, rhodanines, and arylmethines [287,288]. Peptides derived from neuroprotective proteins like NAP (amino acid sequence NAPVSIPQ) and d -SAL (all D-amino acid sequence SALLRSIPA) [289,290], enantiomeric peptides [291], and RNA/DNA aptamers [292] are also attractive components of future anti-tauopathy therapies. Some natural molecules present in cellular medium, such vitamin B 12 [293] and 8-nitro- C GMP [294], are known to inhibit tau aggregation through oxidation of its cysteine residues.…”

From Nose to Brain: The Promise of Peptide Therapy for Alzheimer’s Disease and Other Neurodegenerative Diseases

“…One D-peptide, with the sequence TLKIVW, was designed based on computer modeling [32]. Several 12-mer D-peptides were screened from a peptide library using the mirror image phase display technique [33]. These anti-tau peptides are protease resistant, as they are composed only of D-amino acids, but have not yet been tested on animal models.…”