This project has as its main goal a full understanding of the binding event, and of binding sites in proteins for at least three currently used anesthetic chemotypes, haloalkanes, haloethers and alkylphenols. This includes an understanding of the features underlying binding energetics (affinity) and selectivity, as well as a characterization of the distribution of such sites in specific proteins, like ion channels. We will accomplish these ambitious goals through two specific aims.
Aim 1 is to design, synthesize and characterize novel chemical tools to discover anesthetic binding sites in complex heteroligomeric ion channel proteins.
Aim 2 will deploy these tools, such as the very successful general anesthetic photolabels, in both ligand and voltage gated ion channels. This latter work both provides and directly tests hypotheses in the other projects. The long range goal is to understand features ofthe ligand and ofthe binding site that underlie selectivity so that the compounds can be altered to enhance on-pathway effects and/or to reduce off-pathway effects. Overall, project 1 is a translational conduit of program derived information to clinical relevance.

Public Health Relevance

General anesthetics are delivered to patients roughly 120 million times per year, world wide. They are the most toxic of all drugs physicians use, and have many troublesome side effects, some durable. This project seeks an understanding of their action through the binding event, and using this information will identify novel chemotypes as the basis for the next generation of general anesthetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM055876-15
Application #
8740494
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
15
Fiscal Year
2014
Total Cost
$298,376
Indirect Cost
$99,269
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bensel, Brandon M; Guzik-Lendrum, Stephanie; Masucci, Erin M et al. (2017) Common general anesthetic propofol impairs kinesin processivity. Proc Natl Acad Sci U S A 114:E4281-E4287
Okuno, Toshiaki; Koutsogiannaki, Sophia; Ohba, Mai et al. (2017) Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production. FASEB J 31:1584-1594
Carnevale, Vincenzo; Klein, Michael L (2017) Small molecule modulation of voltage gated sodium channels. Curr Opin Struct Biol 43:156-162
Woll, Kellie A; Skinner, Kenneth A; Gianti, Eleonora et al. (2017) Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling. Biophys J 113:2168-2172
Meng, Tao; Bu, Weiming; Ren, Xianfeng et al. (2016) Molecular mechanism of anesthetic-induced depression of myocardial contraction. FASEB J 30:2915-25
Woll, Kellie A; Murlidaran, Sruthi; Pinch, Benika J et al. (2016) A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of ?-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes. J Biol Chem 291:20473-86
Granata, Daniele; Carnevale, Vincenzo (2016) Accurate Estimation of the Intrinsic Dimension Using Graph Distances: Unraveling the Geometric Complexity of Datasets. Sci Rep 6:31377
Elokely, Khaled; Velisetty, Phanindra; Delemotte, Lucie et al. (2016) Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proc Natl Acad Sci U S A 113:E137-45
Woll, Kellie A; Dailey, William P; Brannigan, Grace et al. (2016) Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands. Anesth Analg 123:1253-1262
Kinde, Monica N; Bondarenko, Vasyl; Granata, Daniele et al. (2016) Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac. Proc Natl Acad Sci U S A 113:13762-13767

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