Journal article
Modulating inhibitors of transthyretin fibrillogenesis via sulfation: polychlorinated biphenyl sulfates as models
Chemico-biological interactions, Vol.228, pp.1-8
02/25/2015
DOI: 10.1016/j.cbi.2015.01.002
PMCID: PMC4327905
PMID: 25595224
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.
Details
- Title: Subtitle
- Modulating inhibitors of transthyretin fibrillogenesis via sulfation: polychlorinated biphenyl sulfates as models
- Creators
- Fabian A Grimm - 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, USAHans-Joachim Lehmler - 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, USAXianran He - Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, Iowa City, IA, USALarry W Robertson - 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, USAMichael W Duffel - 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
- Resource Type
- Journal article
- Publication Details
- Chemico-biological interactions, Vol.228, pp.1-8
- DOI
- 10.1016/j.cbi.2015.01.002
- PMID
- 25595224
- PMCID
- PMC4327905
- NLM abbreviation
- Chem Biol Interact
- ISSN
- 0009-2797
- eISSN
- 1872-7786
- Publisher
- Ireland
- Grant note
- P42 ES013661 / NIEHS NIH HHS P30 ES005605 / NIEHS NIH HHS NIEHS/ NIH P30 ES05605 / NIEHS NIH HHS
- Language
- English
- Date published
- 02/25/2015
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984001083102771
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