Thermodynamically Stable, Photoreversible Pharmacology in Neurons with One‐ and Two‐Photon Excitation

Passlick, Stefan; Richers, Matthew T.; Ellis‐Davies, Graham C. R.

doi:10.1002/ange.201807880

Cited by 11 publications

(14 citation statements)

References 43 publications

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“…In DMSO, the cis−trans switch occurred efficiently by irradiation at 415 nm (Figure 3B), producing a photostationary state (PSS) consisting of 95% trans-photoPROTAC-1 as determined by separation of both isomers via HPLC (Figure 3C). Irradiation at 530 nm established a PSS consisting of 68% cis-photoPROTAC-1, which is slightly reduced when compared to examples of o-F 4 -azobenzenes with higher cis-PSSs 27,41 although the n−π* absorption maxima of both isomers are well-separated by 47 nm (Figure S7 for calculated spectra of pure cis-and trans-photoPROTAC-1).…”

Section: ■ Resultsmentioning

confidence: 98%

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

et al. 2019

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Off-tissue effects are persistent issues of modern inhibition-based therapies. By merging the strategies of photopharmacology and small-molecule degraders, we introduce a novel concept for persistent spatiotemporal control of induced protein degradation that potentially prevents off-tissue toxicity. Building on the successful principle of bifunctional all-small-molecule Proteolysis Targeting Chimeras (PROTACs), we designed photoswitchable PROTACs (photoPROTACs) by including ortho-F4-azobenzene linkers between both warhead ligands. This highly bistable yet photoswitchable structural component leads to reversible control over the topological distance between both ligands. The azo-cis-isomer is observed to be inactive because the distance defined by the linker is prohibitively short to permit complex formation between the protein binding partners. By contrast, the azo-trans-isomer is active since it can engage both protein partners to form the necessary and productive ternary complex. Importantly, due to the bistable nature of the ortho-F4-azobenzene moiety employed, the photostationary state of the photoPROTAC is persistent, with no need for continuous irradiation. This technique offers reversible on/off switching of protein degradation that is compatible with an intracellular environment and, therefore, could be useful in experimental exploration of biological signaling pathways—such as those crucial for oncogenic signal transduction. Additionally, this strategy may be suitable for therapeutic intervention to address a variety of diseases. By enabling reversible activation and deactivation of protein degradation, photoPROTACs offer advantages over conventional photocaging strategies that irreversibly release active agents.

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Section: ■ Resultsmentioning

confidence: 98%

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

et al. 2019

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“…It is worth noting that even under NIR excitation PAI maintains an outstanding potency (picomolar) to activate M2 mAChRs, which is rarely observed in photoswitches. 11,44,47,48 Interestingly, 2P microscopy is extensively used for intravital imaging including cardiovascular imaging at subcellular resolution. 49,50 Thus, PAI has a bright future to control cardiac function with light.…”

Section: Pai Enables Reversible Photocontrol Of Cardiac Activity In Xmentioning

confidence: 99%

Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist

et al. 2019

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Light-triggered reversible modulation of physiological functions offers the promise of enabling on-demand spatiotemporally controlled therapeutic interventions. Optogenetics has been successfully implemented in the heart, but significant barriers to its use in the clinic remain, such as the need for genetic transfection. Herein, we present a method to modulate cardiac function with light through a photoswitchable compound and without genetic manipulation. The molecule, named PAI, was designed by introduction of a photoswitch into the molecular structure of an M2 mAChR agonist. In vitro assays revealed that PAI enables light-dependent activation of M2 mAChRs. To validate the method, we show that PAI photoisomers display different cardiac effects in a mammalian animal model, and demonstrate reversible, real-time photocontrol of cardiac function in translucent wildtype tadpoles. PAI can also effectively activate M2 receptors using two-photon excitation with near-infrared light, which overcomes the scattering and low penetration of short-wavelength illumination, and offers new opportunities for intravital imaging and control of cardiac function.

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“…40,41 Additionally, taking advantage of two-photon excitation processes may further enable switching in a more favorable window. 42,27 Applications of our photoPROTAC method targeting proteins beyond BET domains are currently under investigation and will be reported in due course. This also includes engagement of other E3 ligases such as cereblon or MDM2.…”

Section: Results Synthetic Efforts Commenced With the Generation Of mentioning

confidence: 99%

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable photoPROTACs

Pfaff¹,

Samarasinghe²,

Crews³

et al. 2019

Preprint

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Off-target effects are persistent issues of modern inhibition-based therapies. By merging the strategies of photopharmacology and small molecule degraders, we introduce a novel concept for persistent spatiotemporal control of induced protein degradation that potentially prevents off-target toxicity. Building on the successful principle of bifunctional all-small molecule Proteolysis Targeting Chimeras (PROTACs), we designed photoswitchable PROTACs (photoPROTACs) by including ortho-F4-azobenzene linkers between both warhead ligands. This highly bistable yet photoswitchable structural component leads to reversible control over the topological distance between both ligands. The azo-cis-isomer is observed to be inactive because the distance defined by the linker is prohibitively short to permit complex formation between the protein binding partners. By contrast, the azo-trans-isomer is active because it can engage both protein partners to form the necessary and productive ternary complex. Importantly, due to the bistable nature of the ortho-F4-azobenzene moiety employed, the photostationary state of the photoPROTAC is persistent, with no need for continuous irradiation. This technique offers reversible on/off switching of protein degradation that is compatible with an intracellular environment and, therefore, could be vastly useful in experimental probing of biological signaling pathways – especially those crucial for oncogenic signal transduction. Additionally, this strategy may be suitable for therapeutic implementation in a wide variety of disease phenotypes. By enabling reversible activation and deactivation of protein degradation, photoPROTACs offer advantages over conventional photocaging strategies that irreversibly release active agents.

show abstract

Thermodynamically Stable, Photoreversible Pharmacology in Neurons with One‐ and Two‐Photon Excitation

Cited by 11 publications

References 43 publications

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs

Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist

Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable photoPROTACs

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