Multifunctional Anti-Amyloid Peptides

Aberrant amyloid self-assembly and cytotoxicity of Aß and a-Synuclein are linked to the pathogenesis of more than 50 cell-and neurodegenerative diseases including Alzheimer's (AD), Parkinson’s disease (PD) and type 2 diabetes (T2D), the latter being epidemiologically linked to both AD and PD. For this reason, there is an urgent need to develop molecules that suppress both amyloid self-assembly and cross-seeding interactions of above peptides can be promising leads for therapeutics in AD, PD and T2D. AD-and PD-related neurodegeneration in the brain are linked to the self-assembly of Aß and a-Synuclein while T2D-related pancreatic beta-cell degeneration is linked with amyloid self-assembly of IAPP. Cross-seeding interactions between different amyloid polypeptides/proteins have emerged as possible molecular links between various different cell-/neurodegenerative diseases. Molecules that suppress both amyloid self-assembly and cross-seeding are urgently needed, however.

The results suggest that the anti-amyloid function of MCIP 2 b and 2 e is mediated via interactions with αSyn via three αSyn segments identified as key sites of both αSyn self- and its cross-interactions with IAPP. MCIP  2b and 2 e are also able to block Aβ42-mediated cross-seeding of αSyn. Based on their broad spectrum amyloid inhibitor activity and additional drug-like properties, MCIPs are promising leads for multifunctional anti-amyloid drugs in PD, T2D, AD, and their comorbidities. The identified key αSyn segments shall serve as valuable targets for the design of novel, multi-site targeting molecules as effective anti-amyloids in PD and related synucleinopathies.

Macrocyclic peptides designed to mimic IAPP self-/cross-interaction sites and previously found to inhibit amyloidogenesis of IAPP and/or amyloid-β peptide Aβ40(42) of Alzheimer's Disease, are nanomolar inhibitors of both self- and IAPP-cross-seeded amyloid self-assembly of αSyn.

• MCIPs as candidates for treatment of PD, AD and T2D
  
• Good proteolytic stability in human plasma and by brain proteases (in vitro)
• Effective crossing of human blood brain barrier (cell model)
• Animal studies for PD underway - promising in vivo data in AD mouse model (unpublished)

TRL 4