Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential

In mammalian cells, 10 different adenylyl cyclases produce the ubiquitous second messenger, cyclic adenosine monophosphate (cAMP). Amongst these cAMP-generating enzymes, bicarbonate (HCO(3) (−))-regulated soluble adenylyl cyclase (sAC; ADCY10) is uniquely essential in sperm for reproduction. For thi...

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Autores principales: Rossetti, Thomas, Ferreira, Jacob, Ghanem, Lubna, Buck, Hannes, Steegborn, Clemens, Myers, Robert W., Meinke, Peter T., Levin, Lonny R., Buck, Jochen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Physiology
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9554468/
https://www.ncbi.nlm.nih.gov/pubmed/36246105
http://dx.doi.org/10.3389/fphys.2022.1013845
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author Rossetti, Thomas
Ferreira, Jacob
Ghanem, Lubna
Buck, Hannes
Steegborn, Clemens
Myers, Robert W.
Meinke, Peter T.
Levin, Lonny R.
Buck, Jochen
author_facet Rossetti, Thomas
Ferreira, Jacob
Ghanem, Lubna
Buck, Hannes
Steegborn, Clemens
Myers, Robert W.
Meinke, Peter T.
Levin, Lonny R.
Buck, Jochen
author_sort Rossetti, Thomas
collection PubMed
description In mammalian cells, 10 different adenylyl cyclases produce the ubiquitous second messenger, cyclic adenosine monophosphate (cAMP). Amongst these cAMP-generating enzymes, bicarbonate (HCO(3) (−))-regulated soluble adenylyl cyclase (sAC; ADCY10) is uniquely essential in sperm for reproduction. For this reason, sAC has been proposed as a potential therapeutic target for non-hormonal contraceptives for men. Here, we describe key sAC-focused in vitro assays to identify and characterize sAC inhibitors for therapeutic use. The affinity and binding kinetics of an inhibitor can greatly influence in vivo efficacy, therefore, we developed improved assays for assessing these efficacy defining features.
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spelling pubmed-95544682022-10-13 Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential Rossetti, Thomas Ferreira, Jacob Ghanem, Lubna Buck, Hannes Steegborn, Clemens Myers, Robert W. Meinke, Peter T. Levin, Lonny R. Buck, Jochen Front Physiol Physiology In mammalian cells, 10 different adenylyl cyclases produce the ubiquitous second messenger, cyclic adenosine monophosphate (cAMP). Amongst these cAMP-generating enzymes, bicarbonate (HCO(3) (−))-regulated soluble adenylyl cyclase (sAC; ADCY10) is uniquely essential in sperm for reproduction. For this reason, sAC has been proposed as a potential therapeutic target for non-hormonal contraceptives for men. Here, we describe key sAC-focused in vitro assays to identify and characterize sAC inhibitors for therapeutic use. The affinity and binding kinetics of an inhibitor can greatly influence in vivo efficacy, therefore, we developed improved assays for assessing these efficacy defining features. Frontiers Media S.A. 2022-09-28 /pmc/articles/PMC9554468/ /pubmed/36246105 http://dx.doi.org/10.3389/fphys.2022.1013845 Text en Copyright © 2022 Rossetti, Ferreira, Ghanem, Buck, Steegborn, Myers, Meinke, Levin and Buck. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Rossetti, Thomas
Ferreira, Jacob
Ghanem, Lubna
Buck, Hannes
Steegborn, Clemens
Myers, Robert W.
Meinke, Peter T.
Levin, Lonny R.
Buck, Jochen
Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential
title Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential
title_full Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential
title_fullStr Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential
title_full_unstemmed Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential
title_short Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential
title_sort assessing potency and binding kinetics of soluble adenylyl cyclase (sac) inhibitors to maximize therapeutic potential
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9554468/
https://www.ncbi.nlm.nih.gov/pubmed/36246105
http://dx.doi.org/10.3389/fphys.2022.1013845
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