Substituted organosiloxanes as potential therapeutics for treatment and prevention of neurodegenerative diseases.
Extensive testing of hydrolysates of commercially available organosilanes has identified a number of bifunctional organosiloxane compounds that show potential as therapeutics for treatment of diseases characterized by amyloid deposition such as Alzheimer's disease (AD). All of these compounds protect from and/or reverse the metal-induced aggregation of amyloid Abeta(1-42) peptide in dynamic light scattering (DLS) assays in trifluoroethanol (TFE) solutions, protect from and/or reverse the metal-induced loss of alpha-helical structure in TFE solutions of amyloid Abeta(1-42) as measured by circular dichroism (CD), and are able to cross blood-brain barrier models at rates above background using Caco-2 and MDCK cell permeation assays. Based on these studies, we conclude that members of this class of bifunctional organosiloxanes are promising candidates for testing in treatment and/or prevention of AD and other diseases characterized by amyloid deposition.
Friedman
Orrie M
OM
GrenPharma LLC, 415 South St., MS 015, Waltham, MA 02454, USA.
Matsudaira
Paul
P
Reis
Arthur H
AH
Simister
Neil
N
Correia
Ivan
I
Kew
David
D
Wei
Julie Y
JY
Pochapsky
Thomas
T
D000544:Alzheimer Disease / Q000378:metabolism / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D002942:Circular Dichroism / Q000379:methods; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000517:prevention & control*; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D012833:Siloxanes / Q000627:therapeutic use*; D014270:Trifluoroethanol / Q000494:pharmacology / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012833:Siloxanes; C075222:amyloid beta-protein (1-42); D014270:Trifluoroethanol