Small-molecule aggregates inhibit amyloid polymerization.
Many amyloid inhibitors resemble molecules that form chemical aggregates, which are known to inhibit many proteins. Eight known chemical aggregators inhibited amyloid formation of the yeast and mouse prion proteins Sup35 and recMoPrP in a manner characteristic of colloidal inhibition. Similarly, three known anti-amyloid molecules inhibited beta-lactamase in a detergent-dependent manner, which suggests that they too form colloidal aggregates. The colloids localized to preformed fibers and prevented new fiber formation in electron micrographs. They also blocked infection of yeast cells with Sup35 prions, which suggests that colloidal inhibition may be relevant in more biological milieus.
Feng
Brian Y
BY
Department of Pharmaceutical Chemistry and Graduate Group in Chemistry and Chemical Biology, University of California San Francisco, 1700 4th Street, San Francisco, California 94158-2330, USA.
Toyama
Brandon H
BH
Wille
Holger
H
Colby
David W
DW
Collins
Sean R
SR
May
Barnaby C H
BC
Prusiner
Stanley B
SB
Weissman
Jonathan
J
Shoichet
Brian K
BK
D000098:Acetophenones / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D007464:Clioquinol / Q000737:chemistry / Q000494:pharmacology*; D003224:Congo Red / Q000737:chemistry / Q000494:pharmacology*; D003902:Detergents / Q000737:chemistry; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D015394:Molecular Structure; D008970:Molecular Weight; D010316:Particle Size; D010454:Peptide Termination Factors; D010635:Phenolphthaleins / Q000737:chemistry / Q000494:pharmacology*; D010797:Phthalimides / Q000737:chemistry / Q000494:pharmacology*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry
C117146:4,5-bis(4-fluoroanilino)phthalimide; D000098:Acetophenones; D001578:Benzopyrans; D003902:Detergents; D044950:Flavanones; D010454:Peptide Termination Factors; D010635:Phenolphthaleins; D010797:Phthalimides; D011328:Prions; D011994:Recombinant Proteins; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D065093:beta-Lactamase Inhibitors; C531044:tetraiodophenolphthalein; D003224:Congo Red; C006680:baicalein; D007464:Clioquinol; C085746:rottlerin; D001618:beta-Lactamases