title: Molecular Design for Dual Modulation Effect of Amyloid Protein Aggregation.
abstract: Modulation of protein self-assembly has been a powerful strategy for controlling and understanding amyloid protein aggregation. Most modulators of amyloid aggregation only involve simple inhibition or acceleration. Here we report a new multivalent molecular motif, the polyethylenimine-perphenazine (PEI-P) conjugate which has a dual "acceleration-inhibition" modulation effect on amyloid β (Aβ) aggregation. Dose dependent results from Thioflavin T fluorescence assays, circular dichroism, and atomic force microscopy show that PEI-P conjugates accelerate formation of Aβ prefibrillar intermediates and then inhibit Aβ fibrillation. Furthermore, compared to perphenazine alone, PEI-P conjugates exhibit an enhanced inhibitory effect due to multivalency. Cell viability assays indicate that the PEI-P conjugates reduce the cytotoxicity of Aβ aggregates in a dose-dependent manner. This new modulation strategy may shed light on controlling amyloid aggregation, which offers a general concept for designing new modulators.
authors.affiliation: Department of Chemistry and Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Chemistry and Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Chemistry and Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Pin-Nan
authors.initials: PN
authors.lastname: Cheng
authors.affiliation: Department of Chemistry and Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Moore
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D002942:Circular Dichroism; D015195:Drug Design; D006801:Humans; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D010546:Perphenazine / Q000737:chemistry / Q000494:pharmacology*; D011094:Polyethyleneimine / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D066329:Protein Aggregates; D011094:Polyethyleneimine; D010546:Perphenazine