@article{ccdaac0977494644996472bffdb36ee0,
title = "Multivalent Polymer-Peptide Conjugates: A General Platform for Inhibiting Amyloid Beta Peptide Aggregation",
abstract = "Protein aggregation is implicated in multiple deposition diseases including Alzheimer's Disease, which features the formation of toxic aggregates of amyloid beta (Aβ) peptides. Many inhibitors have been developed to impede or reverse Aβ aggregation. Multivalent inhibitors, however, have been largely overlooked despite the promise of high inhibition efficiency endowed by the multivalent nature of Aβ aggregates. In this work, we report the success of multivalent polymer-peptide conjugates (mPPCs) as a general class of inhibitors of the aggregation of Aβ40. 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 7% ligand loading across different MWs. Molecular dynamics simulations along with dynamic light scattering experiments suggest{\^a}»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 Aβ peptides, and impair the overall inhibition potency.",
author = "Xing Jiang and Halmes, {Abigail J.} and Giuseppe Licari and Smith, {John W.} and Yang Song and Moore, {Edwin G.} and Qian Chen and Emad Tajkhorshid and Rienstra, {Chad M.} and Moore, {Jeffrey S.}",
note = "Funding Information: This research is supported by funding from the Arnold and Mabel Beckman Foundation (Beckman Institute Postdoctoral Fellowship University of Illinois, Urbanaa-Champaign, X.J.), the U.S. Air Force Office of Scientific Research Young Investigator Program (AFOSR-YIP FA9550-17-1-0296, Q.C.) and Defense University Research Instrumentation Program (FA9550-18-1-0393, Q.C.), National Institutes of Health (P41-GM104601 R01-GM123455, and R01-GM067887, E.T.; R01-GM123455, C.M.R.), and the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering (Award No. DE-FG02-07ER46471 J.S.M). Simulations were performed using National Science Foundation computing resources allocated through an XSEDE grant (MCA06N060, E.T.) and Illinois Blue Waters allocation (to E.T.) at the National Center for Supercomputing Applications at the University of Illinois. We thank Shijia Tang and Liuyan Tang for their assistance and discussions and Prof. Cathy Murphy for access to the DLS instrument.*%blankline%**%blankline%* Funding Information: This research is supported by funding from the Arnold and Mabel Beckman Foundation (Beckman Institute Postdoctoral Fellowship, University of Illinois, Urbana–Champaign, X.J.), the U.S. Air Force Office of Scientific Research Young Investigator Program (AFOSR-YIP, FA9550-17-1-0296, Q.C.) and Defense University Research Instrumentation Program (FA9550-18-1-0393, Q.C.), National Institutes of Health (P41-GM104601, R01-GM123455, and R01-GM067887, E.T.; R01-GM123455, C.M.R.), and the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering (Award No. DE-FG02-07ER46471, J.S.M). Simulations were performed using National Science Foundation computing resources allocated through an XSEDE grant (MCA06N060, E.T.) and Illinois Blue Waters allocation (to E.T.) at the National Center for Supercomputing Applications at the University of Illinois. We thank Shijia Tang and Liuyan Tang for their assistance and discussions and Prof. Cathy Murphy for access to the DLS instrument. Publisher Copyright: Copyright {\textcopyright} 2019 American Chemical Society.",
year = "2019",
month = oct,
day = "15",
doi = "10.1021/acsmacrolett.9b00559",
language = "English (US)",
volume = "8",
pages = "1365--1371",
journal = "ACS Macro Letters",
issn = "2161-1653",
publisher = "American Chemical Society",
number = "10",
}