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Novel enhancers of guanylyl cyclase-A activity via allosteric modulation
Open accessPreprint — published as 10.1111/bph.16203
Abstract
Natriuretic peptide receptor (NPR)-A (also known as NPR-A, NPR1 or guanylyl cyclase-A, GC-A) is an attractive but challenging target to activate with small molecules. GC-A is activated by endogenous atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), and this activation leads to the production of 3’,5’-cyclic guanosine monophosphate (cGMP). This system plays an important role in the regulation of cardiovascular and renal homeostasis. However, utilization of this receptor as a drug target has so far been limited to peptides, even though small molecule modulators allow oral administration and longer half-life. We have identified small molecular allosteric enhancers of GC-A, which strengthened ANP or BNP activation in various in vitro and ex vivo systems. These compounds do not mediate their actions through previously described allosteric binding sites or via known mechanisms of action. In addition, their selectivity and activity are dependent on only one amino acid in GC-A. Our findings show that there is a novel allosteric binding site on GC-A, which can be targeted by small molecules that increase the signaling effects of ANP and BNP.
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Metadata
- Authors
- Andresen, H., Pérez-Ternero, C., Robinson, J., Dickey, D. M., Hobbs, A. J., Potter, L. R., Levy, F. O., Cataliotti, A., & Moltzau, L. R.
- Affiliations
- Oslo University Hospital (NO)
- University of Minnesota (US)
- Queen Mary University of London (GB)
- Corresponding author
- Levy, Finn Olav
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- openRxiv
- Published
- 2022-01-01
- Volume
- 180
- Issue
- 24
- Pages
- 3254-3270
- ISSN
- 0007-1188 (ISSN-L)
- PMC
- PMC10952227
- OpenAlex
- W4385406485
- Cited by
- 4
- References
- 1
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1
- FWCI
- 0.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- British Journal of Pharmacology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- Greater South Information System
- Funders
- Wellcome Trust (205167)
- British Heart Foundation (RG/16/7/32357)
- Universitetet i Oslo
- Norges Forskningsråd (285197, 205167, 303490)
- Anders Jahres Fond til Vitenskapens Fremme
- Novo Nordisk Fonden (NNF22OC0080919)
- Nasjonalforeningen for Folkehelsen (460310)
- Helse Sør-Øst RHF (2023045, 2019051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Keywords
- guanylyl cyclase-A, allosteric enhancers, small molecule activators, atrial natriuretic peptide, brain natriuretic peptide, cyclic GMP, vasorelaxation, aorta, allosteric site, cardiovascular disease treatment
- MeSH terms
- Animals, Cyclic GMP, Guanylate Cyclase, Atrial Natriuretic Factor, Rats, Wistar, Receptors, Atrial Natriuretic Factor, Natriuretic Peptide, Brain, Rats
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