Title : Peptide-based inhibitors of amyloid beta aggregation and toxicity as Alzheimer's drug candidates
Abstract:
There are around 35 million individuals affected by Alzheimer’s disease (AD) dementia worldwide, and currently there are no effective disease-modifying medicines for AD. During the last 2.5 decades, four FDA-approved AD drugs, i.e., donepezil, rivastigmine, galantamine, and memantine, have been available. These are symptomatic drugs and do not modulate the underlying disease process. The amyloid beta (A?) peptide and the tau protein, especially its hyperphosphorylated form, have been the major therapeutic targets of AD drug development. Various strategies have been employed, i.e., inhibition of A? production by ?- and ?-secretases, inhibition of A? aggregation, clearance by monoclonal antibodies (mAbs), immunization, inhibition of tau phosphorylation etc. Two anti-A? mAbs, aducanumab and lecanemab, have been recently approved by FDA (June 2021 and January 2023, respectively), but their disease-modifying potency remains questionable. Unfortunately, most of AD drug development efforts have failed due to various reasons, e.g. lack of efficacy of adverse events such as edema or cerebral hemorrhage.
Despite the evidence that peptides and peptidomimetics have shown strong potential in inhibiting A? aggregation and cytotoxicity, peptide-based compounds are not recruited as potential AD drugs. This presentation will address this gap by identifying peptide sequences with superior capabilities of inhibiting A? aggregation and cytotoxicity that may become effective AD drug candidates.
Peptides unrelated to A? (e.g., YAibWF, RYYAAFFARR, NAVRWSLMRPF) or corresponding to defined stretches of A?, e.g., A?16-22 (KLVFFAE), strongly inhibited A? aggregation and toxicity. Our research group has recently analyzed the influence of overlapping 10- to 12-residue fragments of A?1-42 on the aggregation of the parent peptide (Abedin F, Kandel N, Tatulian SA. Sci Rep (2021) 11:19262). A?11-20 (P3) and A?26-36 (P6) inhibited the aggregation of A?1-42 by 80-90%. Moreover, P3 and P6 totally impeded A?1-42 toxicity to PC-12 cells at 2-fold molar excess, identifying these peptides as potential AD drug candidates.
Obstacles in delivery of peptides to the brain parenchyma, such as the blood-brain barrier (BBB) or hydrolysis by gastrointestinal or plasma enzymes, can be mitigated by methods like cyclization or N- and Cterminal capping, mutations that remove the cleavage site(s), intracerebroventricular infusion, nasal administration, or permeabilization of the BBB by focused ultrasound. Thus, short peptides emerge as potent inhibitors of A? aggregation and cytotoxicity, with strong potential for becoming viable AD drugs.
Audience Takeaway:
- Researchers may use the information to explore other peptides to identify strong inhibitors of A? aggregation and cytotoxicity.
- The material presented here can be used by other scholars to expand their research or teaching by involving peptides as modulators of A? in both their research and teaching.
- Using peptides that are modified by capping or cyclization may offer solutions to metabolic instability and cell permeation of the peptides.
