Xing Jiang, Abigail J. Halmes, Giuseppe Licari, John W. Smith, Yang Song,
Edwin G. Moore, Qian Chen, Emad Tajkhorshid, Chad M. Rienstra, and Jeffrey S.
Moore.
Multivalent polymer-peptide conjugates: A general platform for
inhibiting amyloid beta peptide aggregation.
ACS Macro Letters, 8:1365-1371, 2019.
(PMC: PMC7059649)
JIAN2019A-ET
Protein aggregation is implicated in multiple deposition diseases including
Alzheimer’s Disease, which
features the formation of toxic aggregates of amyloid beta (A-beta) peptides.
Many inhibitors have been
developed to impede or reverse A-beta aggregation. Multivalent inhibitors,
however, have been largely
overlooked despite the promise of high inhibition efficiency endowed by the
multivalent nature
of A-beta aggregates. In this work, we report the success of multivalent
polymer-peptide conjugates
(mPPCs) as a general class of inhibitors of the aggregation of A-beta-40.
Significantly delayed onset of
fibril formation was realized using mPPCs prepared with three peptide/peptoid
ligands
covering a range of polymer molecular weights (MWs) and ligand loadings.
Dose dependence studies
showed that the nature of the ligands is a key factor in mPPC inhibition potency.
The negatively charged
ligand LPFFD leads to more efficient mPPCs compared to mPPCs with the
neutral ligands, and is most
effective at 7simulations along with dynamic
light scattering experiments suggest that mPPCs form globular structures in
solution due to ligand-ligand
interactions. Such interactions are key to the spatial proximity of ligands and
thus to the multivalency
effect of mPPC inhibition. Excess ligand-ligand interactions, however, reduce
the accessibility of mPPC
ligands to A-beta peptides, and impair the overall inhibition potency.
