Multivalent Polymer-Peptide Conjugates-A General Platform for Inhibiting Amyloid Beta Peptide Aggregation.

Area of Science:

• Biochemistry
• Polymer Science
• Neuroscience

Background:

• Protein aggregation, particularly amyloid beta (Aβ) peptides, is central to neurodegenerative diseases like Alzheimer's Disease.
• Existing inhibitors often target Aβ aggregation, but multivalent strategies remain underexplored.
• Aβ aggregates possess inherent multivalency, suggesting potential for highly efficient multivalent inhibitors.

Purpose of the Study:

• To investigate multivalent polymer-peptide conjugates (mPPCs) as a novel class of inhibitors for amyloid beta (Aβ)₄₀ aggregation.
• To explore the impact of polymer molecular weight, ligand type, and ligand loading on mPPC inhibition efficiency.
• To elucidate the structural basis for mPPC inhibition through computational and experimental methods.

Main Methods:

• Synthesis of mPPCs using three distinct peptide/peptoid ligands with varying polymer molecular weights and ligand loadings.
• Assessment of Aβ₄₀ aggregation kinetics using techniques like dynamic light scattering.
• Molecular dynamics simulations to investigate mPPC structure and interactions in solution.
• Dose-response studies to determine the potency of different mPPC formulations.

Main Results:

• mPPCs significantly delayed the onset of Aβ₄₀ fibril formation across tested configurations.
• Inhibition potency was strongly dependent on ligand type, with negatively charged ligands showing superior performance.
• Optimal inhibition was observed at 7% ligand loading for the negatively charged ligand, irrespective of polymer molecular weight.
• Molecular dynamics and DLS experiments indicated that mPPCs form globular structures driven by ligand-ligand interactions, crucial for multivalency.

Conclusions:

• mPPCs represent a promising general class of inhibitors for Aβ₄₀ aggregation.
• Ligand properties and loading are critical determinants of mPPC efficacy.
• Intramolecular ligand-ligand interactions within mPPCs are key to their multivalent inhibitory mechanism, though excessive interactions can reduce efficacy.