Andresen, Henriette;
Perez-Ternero, Cristina;
Robinson, Jerid;
Dickey, Deborah M;
Hobbs, Adrian J;
Potter, Lincoln R;
Levy, Finn Olav;
... Moltzau, Lise Roman; + view all
(2023)
Novel enhancers of guanylyl cyclase-A activity acting via allosteric modulation.
British Journal of Pharmacology
, 180
(24)
pp. 3254-3270.
10.1111/bph.16203.
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Abstract
Background and Purpose: Guanylyl cyclase-A (GC-A), activated by endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), plays an important role in the regulation of cardiovascular and renal homeostasis and is an attractive drug target. Even though small molecule modulators allow oral administration and longer half-life, drug targeting of GC-A has so far been limited to peptides. Thus, in this study we aimed to develop small molecular activators of GC-A. Experimental Approach: Hits were identified through high-throughput screening and optimized by in silico design. Cyclic GMP was measured in QBIHEK293A cells expressing GC-A, GC-B or chimerae of the two receptors using AlphaScreen technology. Binding assays were performed in membrane preparations or whole cells using <sup>125</sup>I-ANP. Vasorelaxation was measured in aortic rings isolated from Wistar rats. Key Results: We have identified small molecular allosteric enhancers of GC-A, which enhanced ANP or BNP effects in cellular systems and ANP-induced vasorelaxation in rat aortic rings. The mechanism of action appears novel and not mediated through previously described allosteric binding sites. In addition, the selectivity and activity depend on a single amino acid residue that differs between the two similar receptors GC-A and GC-B. Conclusion and Implications: We describe a novel allosteric binding site on GC-A, which can be targeted by small molecules to enhance ANP and BNP effects. These compounds will be valuable tools in further development and proof-of-concept of GC-A enhancement for the potential use in cardiovascular therapy.
| Type: | Article |
|---|---|
| Title: | Novel enhancers of guanylyl cyclase-A activity acting via allosteric modulation |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bph.16203 |
| Publisher version: | https://doi.org/10.1111/bph.16203 |
| Language: | English |
| Additional information: | © 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | allosteric modulation, cardiovascular pharmacology, drug discovery/target validation, guanylyl cyclase, natriuretic peptides |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217553 |
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