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The stereospecific interaction sites and target specificity of cGMP analogs in mouse cortex

Rasmussen, Michel LU ; Welinder, Charlotte LU ; Schwede, Frank and Ekström, Per LU (2022) In Chemical Biology and Drug Design 99(2). p.206-221
Abstract

cGMP interactors play a role in several pathologies and may be targets for cGMP analog-based drugs, but the success of targeting depends on the biochemical stereospecificity between the cGMP-analog and the interactor. The stereospecificity between general cGMP analogs—or such that are selectivity-modified to obtain, for example, inhibitory actions on a specific target, like the cGMP-dependent protein kinase—have previously been investigated. However, the importance of stereospecificity for cGMP-analog binding to interactors is not known. We, therefore, applied affinity chromatography on mouse cortex proteins utilizing analogs with cyclic phosphate (8-AET-cGMP, 2-AH-cGMP, 2′-AHC-cGMP) and selectivity-modified analogs with... (More)

cGMP interactors play a role in several pathologies and may be targets for cGMP analog-based drugs, but the success of targeting depends on the biochemical stereospecificity between the cGMP-analog and the interactor. The stereospecificity between general cGMP analogs—or such that are selectivity-modified to obtain, for example, inhibitory actions on a specific target, like the cGMP-dependent protein kinase—have previously been investigated. However, the importance of stereospecificity for cGMP-analog binding to interactors is not known. We, therefore, applied affinity chromatography on mouse cortex proteins utilizing analogs with cyclic phosphate (8-AET-cGMP, 2-AH-cGMP, 2′-AHC-cGMP) and selectivity-modified analogs with sulfur-containing cyclic phosphorothioates (Rp/Sp-8-AET-cGMPS, Rp/Sp-2′-AHC-cGMPS) immobilized to agaroses. The results illustrate the cGMP analogs' stereospecific binding for PKG, PKA regulatory subunits and PKA catalytic subunits, PDEs, and EPAC2 and the involvement of these in various KEGG pathways. For the seven agaroses, PKG, PKA regulatory subunits, and PKA catalytic subunits were more prone to be enriched by 2-AH-, 8-AET-, Rp-8-AET-, and Sp-8-AET-cGMP, whereas PDEs and EPAC2 were more likely to be enriched by 2-AH-, Rp-2′-AHC-, and Rp-8-AET-cGMP. Our findings help elucidate the stereospecific-binding sites essential for the interaction between individual cGMP analogs and cGMP-binding proteins, as well as the cGMP analogs’ target specificity, which are two crucial parameters in drug design.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cGMP-analog, cGMP-binding protein, mouse cortex, proteomic approach, stereospecific interaction site, target specificity
in
Chemical Biology and Drug Design
volume
99
issue
2
pages
206 - 221
publisher
Wiley-Blackwell
external identifiers
  • pmid:34687134
  • scopus:85117957425
ISSN
1747-0277
DOI
10.1111/cbdd.13976
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021 The Authors. Chemical Biology & Drug Design published by John Wiley & Sons Ltd.
id
5355a7d6-5ea5-490b-abe1-6b4290177636
date added to LUP
2021-11-24 08:49:50
date last changed
2024-04-06 14:05:34
@article{5355a7d6-5ea5-490b-abe1-6b4290177636,
  abstract     = {{<p>cGMP interactors play a role in several pathologies and may be targets for cGMP analog-based drugs, but the success of targeting depends on the biochemical stereospecificity between the cGMP-analog and the interactor. The stereospecificity between general cGMP analogs—or such that are selectivity-modified to obtain, for example, inhibitory actions on a specific target, like the cGMP-dependent protein kinase—have previously been investigated. However, the importance of stereospecificity for cGMP-analog binding to interactors is not known. We, therefore, applied affinity chromatography on mouse cortex proteins utilizing analogs with cyclic phosphate (8-AET-cGMP, 2-AH-cGMP, 2′-AHC-cGMP) and selectivity-modified analogs with sulfur-containing cyclic phosphorothioates (Rp/Sp-8-AET-cGMPS, Rp/Sp-2′-AHC-cGMPS) immobilized to agaroses. The results illustrate the cGMP analogs' stereospecific binding for PKG, PKA regulatory subunits and PKA catalytic subunits, PDEs, and EPAC2 and the involvement of these in various KEGG pathways. For the seven agaroses, PKG, PKA regulatory subunits, and PKA catalytic subunits were more prone to be enriched by 2-AH-, 8-AET-, Rp-8-AET-, and Sp-8-AET-cGMP, whereas PDEs and EPAC2 were more likely to be enriched by 2-AH-, Rp-2′-AHC-, and Rp-8-AET-cGMP. Our findings help elucidate the stereospecific-binding sites essential for the interaction between individual cGMP analogs and cGMP-binding proteins, as well as the cGMP analogs’ target specificity, which are two crucial parameters in drug design.</p>}},
  author       = {{Rasmussen, Michel and Welinder, Charlotte and Schwede, Frank and Ekström, Per}},
  issn         = {{1747-0277}},
  keywords     = {{cGMP-analog; cGMP-binding protein; mouse cortex; proteomic approach; stereospecific interaction site; target specificity}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{206--221}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Chemical Biology and Drug Design}},
  title        = {{The stereospecific interaction sites and target specificity of cGMP analogs in mouse cortex}},
  url          = {{http://dx.doi.org/10.1111/cbdd.13976}},
  doi          = {{10.1111/cbdd.13976}},
  volume       = {{99}},
  year         = {{2022}},
}