Photoswitchable dynasore analogs to control endocytosis with light

Camarero, Núria; Trapero, Ana; Pérez‐Jiménez, Ariadna; Macia, Eric; Gomila, Alexandre M. J.; Martín‐Quirós, Andrés; Nevola, Laura; Llobet, Artur; Llebaría, Amadeu; Hernando, Jordi; Giralt, Ernest; Gorostiza, Pau

doi:10.1039/d0sc03820b

Cited by 6 publications

(4 citation statements)

References 38 publications

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“…Finally, AMPA receptor desensitization might contribute to the transient response properties. Future work could consider to further speedup thermal relaxation potentially by replacing the current azobenzene unit in TCP fast with faster photoswitches such as (hydroxy-substituted) phenylazopyrimidine (millisecond to nanosecond range − ). However, such accelerated back-switching might in turn result in a lower cis conversion percentage in the photostationary state and, therefore, would require higher light intensity.…”

Section: Discussionmentioning

confidence: 99%

Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea

et al. 2022

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Artificial control of neuronal activity enables the study of neural circuits and restoration of neural functions. Direct, rapid, and sustained photocontrol of intact neurons could overcome the limitations of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors (GluRs) to enable neuronal control in the auditory system. The new photoswitchable ligands induced photocurrents in untransfected neurons upon covalently tethering to endogenous GluRs and activating them reversibly with visible light pulses of a few milliseconds. As a proof of concept of these molecular prostheses, we applied them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method afforded the optical stimulation of auditory neurons of adult gerbils at hundreds of hertz without genetic manipulation that would be required for their optogenetic control. This indicates that the new photoswitchable ligands are also applicable to the spatiotemporal control of fast spiking interneurons in the brain.

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Section: Discussionmentioning

confidence: 99%

Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea

et al. 2022

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“…Moreover, CAPs represent population responses and so light pulses might be recruiting variable subsets of SGNs. Future work could consider to further speed-up thermal relaxation potentially by replacing the current azobenzene unit in TCP fast with faster photoswitches such as (hydroxy-substituted) phenylazopyrimidine (milliseconds to nanoseconds range (Camarero et al , 2020; Čechová et al , 2020; Garcia-Amorós et al , 2012)). However, such accelerated back-switching might in turn result in lower % cis conversion in the photostationary state and, therefore, require higher light intensity.…”

Section: Discussionmentioning

confidence: 99%

Fast photoswitchable molecular prosthetics control neuronal activity in the cochlea

Aida

Antoine

Matera

et al. 2021

Preprint

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Artificial control of neuronal activity enables studies of neural circuits and restoration of neural function. Direct, rapid, and sustained photocontrol of intact neurons could overcome shortcomings of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors to establish such control in the auditory system. The new photoswitchable ligands produced photocurrents in untransfected neurons upon covalently tethering to endogenous glutamate receptors and activating them reversibly with visible light pulses of few milliseconds. As a proof of concept of these molecular prostheses, we apply them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method affords kilohertz rate stimulation of auditory neurons of adult gerbils without genetic manipulation that would be required for their optogenetic control. The new photoswitchable ligands are also broadly applicable to spatiotemporally control fast spiking interneurons in the brain.

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“…[56] The development of the photoswitchable inhibitor 52 has afforded optical control over dynamin activity, in which dynamin-dependent endocytosis was regulated upon ON/OFF exposure to UV light. [57] In efforts to achieve optical control of acid sphingomyelinase (ASM) inhibition, photolabile caging groups were introduced onto the phosphate groups of a known ASM inhibitor, rendering the inhibitor inactive (compound 53). [58] The inclusion of biologically labile butyryl groups on the hydroxy moieties were also needed to enhance cellular uptake.…”

Section: Other Enzymatic Targetsmentioning

confidence: 99%

“…The GTPase, dynamin, plays a critical role in most endocytic pathways [56] . The development of the photoswitchable inhibitor 52 has afforded optical control over dynamin activity, in which dynamin‐dependent endocytosis was regulated upon ON/OFF exposure to UV light [57] …”

Section: Other Enzymatic Targetsmentioning

confidence: 99%

Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity

Laczi

Johnstone

Fleming

2022

Chemistry An Asian Journal

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The development of new and effective therapeutics is reliant on the ability to study the underlying mechanisms of potential drug targets in live cells and multicellular systems. A persistent challenge in many drug development programmes is poor selectivity, which can obscure the mechanisms involved and lead to poorly understood modes of action. In efforts to improve our understanding of these complex processes, small molecule inhibitors have been developed in which their OFF/ON therapeutic activity can be toggled using light. Photopharmacology is devoted to using light to modulate drugs. Herein, we highlight the recent progress made towards the development of light‐responsive small molecule inhibitors of selected enzymatic targets. Given the size of this field, literature from 2015 onwards has been reviewed.

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Photoswitchable dynasore analogs to control endocytosis with light

Abstract: We've combined the pharmacological properties of the dynamin inhibitor dynasore and the photochromic properties of an azobenzene group, to obtain the first light-regulated small-molecule inhibitor of endocytosis.

Cited by 6 publications

References 38 publications

Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea

Fast Photoswitchable Molecular Prosthetics Control Neuronal Activity in the Cochlea

Fast photoswitchable molecular prosthetics control neuronal activity in the cochlea

Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity

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