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Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechanoelectrical transducer channel

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posted on 2023-06-09, 17:52 authored by Molly O'Reilly, Nerissa K Kirkwood, Emma Kenyon, Rosemary Huckvale, Daire Cantillon, Simon WaddellSimon Waddell, Simon E Ward, Guy Richardson, Corne Kros, Marco Derudas
Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell’s mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol itself in cochlear cultures and also to bind more tightly to the MET channel. At higher concentrations, both carvedilol and this derivative were toxic in cochlear cultures but not in zebrafish, suggesting a good therapeutic window under in vivo conditions.

Funding

Mechanisms of aminoglyscoside ototoxicity and drug damage repair in sensory hair cells: towards the design of otoprotective strategies.; G1025; MRC-MEDICAL RESEARCH COUNCIL; MR/K005561/1

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society

Issue

11

Volume

62

Page range

5312-5329

Department affiliated with

  • Global Health and Infection Publications

Research groups affiliated with

  • Wellcome Trust Brighton and Sussex Centre for Global Health Research Publications
  • Sussex Drug Discovery Centre Publications
  • Sussex Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-05-21

First Open Access (FOA) Date

2020-05-19

First Compliant Deposit (FCD) Date

2019-05-20

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