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Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands

Nichols, Aaron L. and Blumenfeld, Zack and Fan, Chengcheng and Luebbert, Laura and Blom, Annet E. M. and Cohen, Bruce N. and Marvin, Jonathan S. and Borden, Philip M. and Kim, Charlene H. and Muthusamy, Anand K. and Shivange, Amol V. and Knox, Hailey J. and Rego Campello, Hugo and Wang, Jonathan H. and Dougherty, Dennis A. and Looger, Loren L. and Gallagher, Timothy and Rees, Douglas C. and Lester, Henry A. (2021) Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20211008-224629724

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Abstract

Nicotinic partial agonists provide a partial aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives – 10-fluorocytisine and 9-bromo-10-ethylcytisine. Development of the series was aided and explained by the first atomic-scale structural studies on liganded periplasmic binding protein-based biosensors. Members of the series detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and primary mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by > 30 fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.10.04.463082DOIDiscussion Paper
ORCID:
AuthorORCID
Nichols, Aaron L.0000-0001-9341-0049
Blumenfeld, Zack0000-0002-4627-5582
Fan, Chengcheng0000-0003-4213-5758
Luebbert, Laura0000-0003-1379-2927
Blom, Annet E. M.0000-0002-7441-4893
Marvin, Jonathan S.0000-0003-2294-4515
Muthusamy, Anand K.0000-0003-1041-914X
Shivange, Amol V.0000-0002-4169-2969
Rego Campello, Hugo0000-0001-8588-0198
Dougherty, Dennis A.0000-0003-1464-2461
Looger, Loren L.0000-0002-7531-1757
Gallagher, Timothy0000-0002-3544-327X
Rees, Douglas C.0000-0003-4073-1185
Lester, Henry A.0000-0002-5470-5255
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Version 1 - October 4, 2021; Version 2 - October 11, 2021; Version 3 - November 3, 2021. We thank Stefan Petrovic for his stewardship of the isothermal titration calorimeter in the Caltech Center for Molecular Medicine, Jens Kaiser for help with structural studies at the Caltech Molecular Observatory, the Gradinaru lab and Caltech CLOVER Center for help with viral vectors, and Andres Collazo and Giada Spigolon at the Caltech Biological Imaging Facility. We thank Zoe Beatty, Kallol Bera, Eve Fine, Shan Huang, Elaine Lin, Stephen Mayo, Lin Tian, and Elizabeth Unger for advice and guidance. We thank Achieve Life Sciences for a gift of cytisine. The authors declare no financial or non-financial competing interests. Funding: California Tobacco-Related Disease Research Program (TRDRP) (27FT-0022), Aaron L. Nichols. California Tobacco-Related Disease Research Program (TRDRP) (27IP-0057), Henry A. Lester. California Tobacco-Related Disease Research Program (TRDRP) (T29IR0455), Dennis A. Dougherty. NIH (GM-123582, DA043829), Henry A. Lester. NIH (DA049140, GM7616), Anand K. Muthusamy. Howard Hughes Medical Institute (Loren L. Looger, Jonathan S. Marvin, Douglas C. Rees). UK Engineering and Physical Sciences Research Council (No. EP/N024117/1), Timothy Gallagher. Leiden University International Studies Fund (LISF L18020-1-45), Laura Luebbert.
Group:Jacobs Institute for Molecular Engineering for Medicine
Funders:
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program27FT-0022
California Tobacco-Related Disease Research Program27IP-0057
California Tobacco-Related Disease Research ProgramT29IR0455
NIHGM-123582
NIHDA043829
NIHDA049140
NIHGM7616
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Engineering and Physical Sciences Research Council (EPSRC)EP/N024117/1
Leiden UniversityLISF L18020-1-45
DOI:10.1101/2021.10.04.463082
Record Number:CaltechAUTHORS:20211008-224629724
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211008-224629724
Official Citation:Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands. Aaron L Nichols, Zack Blumenfeld, Chengcheng Fan, Laura Luebbert, Annet E. M. Blom, Bruce Nathan Cohen, Jonathan S Marvin, Philip M Borden, Charlene Kim, Anand K Muthusamy, Amol V Shivange, Hailey J Knox, Hugo Rego Campello, Jonathan H Wang, Dennis A Dougherty, Loren Looger, Timothy Gallagher, Douglas C Rees, Henry A Lester. bioRxiv 2021.10.04.463082; doi: https://doi.org/10.1101/2021.10.04.463082
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111334
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:11 Oct 2021 21:42
Last Modified:05 Nov 2021 21:09

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