Misfolding & Disease

Therapeutic Strategies Targeting Aggregation Kinetics

Summary

Therapeutic strategies for protein aggregation diseases increasingly target specific microscopic kinetic steps: native state stabilization, inhibiting secondary nucleation, elongation inhibition, and β-sheet breakers.

Key Points

  • 1Tafamidis stabilizes native TTR tetramers
  • 2Secondary nucleation inhibitors reduce toxic oligomer production
  • 3Different diseases require targeting different kinetic steps
  • 4Early intervention is most effective

Modern understanding of aggregation kinetics has revolutionized therapeutic approaches to protein misfolding diseases.

The Kinetic Framework for Therapy

Rather than simply reducing total amyloid load, effective therapies must target the specific microscopic processes that generate toxicity—particularly the production of soluble oligomers.

Key Therapeutic Strategies

1. Native State Stabilization

Principle: Raise the energetic barrier to unfolding, preventing formation of aggregation-prone monomers.

Example: Tafamidis for transthyretin (TTR) amyloidosis

  • Binds the native TTR tetramer
  • Stabilizes the quaternary structure
  • Prevents dissociation into amyloidogenic monomers
  • FDA-approved for TTR cardiomyopathy

    • 2. Inhibiting Secondary Nucleation

    Principle: Block the autocatalytic formation of toxic oligomers on fibril surfaces.

    This is critical for Alzheimer's disease (Aβ):

  • Secondary nucleation produces most toxic oligomers
  • Agents that bind fibril surfaces can block this
  • Specific antibodies targeting fibril surfaces
  • Chaperone domains with surface-binding properties

    • Key insight: This can reduce toxicity without necessarily clearing existing plaques immediately.

    3. Elongation Inhibition

    Principle: "Cap" fibril ends to prevent growth.

  • Small molecules that bind fibril ends
  • Peptides that incorporate but terminate elongation
  • Less effective at reducing oligomer toxicity than nucleation inhibition

    • 4. β-Sheet Breakers

    Principle: Destabilize the cross-β structure of aggregates.

    - Peptidomimetics that bind aggregates

  • Use sequence homology for targeting
  • Sterically disrupt hydrogen bonding
  • Can promote aggregate dissolution

    • Challenges and Considerations

    Timing Matters

  • Early intervention most effective
  • Biomarkers needed for preclinical detection
  • Once extensive damage occurs, reversibility is limited

    • Target Selection

    Success requires identifying which kinetic step dominates toxicity for each specific pathology:

  • Some diseases: primary nucleation-dominated
  • Others: secondary nucleation-dominated
  • The answer determines optimal intervention point

    • Blood-Brain Barrier

    Many promising agents don't cross the BBB:

  • Antibody engineering for CNS penetration
  • Small molecule design
  • Intrathecal delivery options
    • Previous
    Amyloidogenesis and Prion Propagation
    Next
    Pin1 in Alzheimer's Disease Pathology