Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Neuroscience

Background:

• Amyloid self-assembly is implicated in Alzheimer's disease (AD) and type 2 diabetes (T2D) pathogenesis.
• No anti-amyloid compounds have successfully reached clinical application.
• Macrocyclic peptides are promising drug candidates for amyloid-related diseases.

Purpose of the Study:

• To develop novel macrocyclic peptides (MCIPs) as potent inhibitors of amyloid aggregation.
• To investigate the role of chirality in controlling inhibitor selectivity for Aβ40(42) and IAPP.
• To identify MCIPs with desirable drug-like properties, including proteolytic stability and blood-brain barrier (BBB) penetration.

Main Methods:

• Design of MCIPs utilizing minimal IAPP-derived recognition elements.
• Evaluation of inhibitory activity against Aβ40(42) and IAPP amyloid formation.
• Chirality-dependent selectivity studies.
• Assessment of proteolytic stability in human plasma.
• In vitro assessment of BBB crossing ability using a cell model.

Main Results:

• Discovery of MCIPs as nanomolar inhibitors of Aβ40(42) and IAPP aggregation.
• Demonstration that chirality controls the selectivity of MCIPs.
• Identification of an optimized Aβ40(42)-selective MCIP with high proteolytic stability.
• Confirmation of BBB crossing ability for the optimized MCIP in a cell model.

Conclusions:

• MCIPs represent a novel class of potent amyloid inhibitors.
• Chirality is a critical factor in tailoring MCIP selectivity for specific amyloid targets.
• Optimized MCIPs possess favorable pharmacokinetic properties, making them suitable leads for AD drug development.
• MCIPs serve as valuable scaffolds for designing peptidomimetics targeting amyloidogenesis in AD and T2D.