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

Michel Rasmussen, Charlotte Welinder, Frank Schwede, Per Ekström

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)206-221
JournalChemical Biology and Drug Design
Volume99
Issue number2
Early online date2021
DOIs
Publication statusPublished - 2022

Subject classification (UKÄ)

  • Biochemistry and Molecular Biology

Free keywords

  • cGMP-analog
  • cGMP-binding protein
  • mouse cortex
  • proteomic approach
  • stereospecific interaction site
  • target specificity

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