title: Modulating inhibitors of transthyretin fibrillogenesis via sulfation: polychlorinated biphenyl sulfates as models.
abstract: Small molecules that bind with high affinity to thyroxine (T4) binding sites on transthyretin (TTR) kinetically stabilize the protein's tetrameric structure, thereby efficiently decreasing the rate of tetramer dissociation in TTR related amyloidoses. Current research efforts aim to optimize the amyloid inhibiting properties of known inhibitors, such as derivatives of biphenyls, dibenzofurans and benzooxazoles, by chemical modification. In order to test the hypothesis that sulfate group substituents can improve the efficiencies of such inhibitors, we evaluated the potential of six polychlorinated biphenyl sulfates to inhibit TTR amyloid fibril formation in vitro. In addition, we determined their binding orientations and molecular interactions within the T4 binding site by molecular docking simulations. Utilizing this combined experimental and computational approach, we demonstrated that sulfation significantly improves the amyloid inhibiting properties as compared to both parent and hydroxylated PCBs. Importantly, several PCB sulfates were of equal or higher potency than some of the most effective previously described inhibitors.
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, The University of Iowa, Iowa City, IA, USA.
authors.forename: Fabian A
authors.initials: FA
authors.lastname: Grimm
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, Iowa City, IA, USA.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, Iowa City, IA, USA.
authors.forename: Xianran
authors.initials: X
authors.lastname: He
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, Iowa City, IA, USA.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, The University of Iowa, Iowa City, IA, USA. Electronic address: michael-duffel@uiowa.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Duffel
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011228:Prealbumin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D011228:Prealbumin; D013431:Sulfates
keywords: Amyloidosis; PCBs; Polychlorinated biphenyls; Sulfation; TTR; Transthyretin