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
posted on 2023-06-09, 17:52authored byMolly 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