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

Frontiers in Physiology

Physiology

Clemens Steegborn¹  Jochen Buck²  Lonny R. Levin²  Jacob Ferreira²  Lubna Ghanem²  Hannes Buck²  Thomas Rossetti²  Robert W. Myers³  Peter T. Meinke³ 

[1] Department of Biochemistry, University of Bayreuth, Bayreuth, Germany;Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States;Tri-Institutional Therapeutics Discovery Institute, New York, NY, United States;

关键词: soluble adenylyl cyclase;    male contraceptive;    residence time;    drug development;    picomolar potency;    binding kinetics;    lead optimization;    SPR;   

DOI  :  10.3389/fphys.2022.1013845

 received in 2022-08-07, accepted in 2022-09-01,  发布年份 2022

来源: Frontiers

【 摘 要 】

In mammalian cells, 10 different adenylyl cyclases produce the ubiquitous second messenger, cyclic adenosine monophosphate (cAMP). Amongst these cAMP-generating enzymes, bicarbonate (HCO3−)-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.

【 授权许可】

Unknown   
Copyright © 2022 Rossetti, Ferreira, Ghanem, Buck, Steegborn, Myers, Meinke, Levin and Buck.

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