Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity

Laczi, Dóra; Johnstone, Mark D.; Fleming, Cassandra L.

doi:10.1002/asia.202200200

Cited by 17 publications

(12 citation statements)

References 99 publications

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“…Photo-responsive inhibitors have been developed for controlling the activity of a variety of PKs, e.g., PKAcα [ 22 , 45 , 46 ], MLCK [ 45 ], Src [ 29 ], MAPK [ 47 ] and CK1 [ 47 ], to name a few (for a recent review, see [ 2 ]). These inhibitors include photocaged, photoswitchable, and photo-deactivatable variants and the active forms of the inhibitors are mostly either targeting the ATP-binding site or protein-substrate binding site of the PKs.…”

Section: Discussionmentioning

confidence: 99%

“…This not only provides the means for altering the bioactivity at the spatiotemporally focused point, but also allows gradual transformation of the bioactive compound by regulating the amount of energy applied to the system. Most photo-responsive ligands belong to two categories: (1) photocaged or photoactivatable ligands that undergo irreversible activation [ 2 , 3 ] and (2) photoswitchable ligands that can be toggled between the active and deactivated form [ 4 ]. A third category involves ligands that can be (3) irreversibly deactivated by UV-Vis irradiation.…”

Section: Introductionmentioning

confidence: 99%

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Deactivatable Bisubstrate Inhibitors of Protein Kinases

et al. 2022

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Bivalent ligands, including bisubstrate inhibitors, are conjugates of pharmacophores, which simultaneously target two binding sites of the biomolecule. Such structures offer attainable means for the development of compounds whose ability to bind to the biological target could be modulated by an external trigger. In the present work, two deactivatable bisubstrate inhibitors of basophilic protein kinases (PKs) were constructed by conjugating the pharmacophores via linkers that could be cleaved in response to external stimuli. The inhibitor ARC-2121 incorporated a photocleavable nitrodibenzofuran-comprising β-amino acid residue in the structure of the linker. The pharmacophores of the other deactivatable inhibitor ARC-2194 were conjugated via reduction-cleavable disulfide bond. The disassembly of the inhibitors was monitored by HPLC-MS. The affinity and inhibitory potency of the inhibitors toward cAMP-dependent PK (PKAcα) were established by an equilibrium competitive displacement assay and enzyme activity assay, respectively. The deactivatable inhibitors possessed remarkably high 1–2-picomolar affinity toward PKAcα. Irradiation of ARC-2121 with 365 nm UV radiation led to reaction products possessing a 30-fold reduced affinity. The chemical reduction of ARC-2194 resulted in the decrease of affinity of over four orders of magnitude. The deactivatable inhibitors of PKs are valuable tools for the temporal inhibition or capture of these pharmacologically important enzymes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deactivatable Bisubstrate Inhibitors of Protein Kinases

et al. 2022

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“…Therefore, we will not discuss it here. [24] In addition to the design of free stimulus-responsive inhibitors, inhibitors can be directly immobilized onto the surface of enzymes using stimulus-sensitive chemical linkers or polymers, allowing switching enzyme activity on and off more effectively. [25] For example, Trauner et al reversibly regulated CA enzyme activity by covalently attaching an inhibitor to the surface of CA via an azobenzene-based linker.…”

Section: Chembiochemmentioning

confidence: 99%

“…A systematic discussion of light‐responsive small‐molecule inhibitors for the remote control of enzyme activity has been recently reviewed elsewhere. Therefore, we will not discuss it here [24] …”

Section: The Mechanisms Of Enzyme Activity Regulationmentioning

confidence: 99%

Advanced Strategies of Enzyme Activity Regulation for Biomedical Applications

2022

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Enzymes are important macromolecular biocatalysts that accelerate chemical and biochemical reactions in living organisms. Most human diseases are related to alterations in enzyme activity. Moreover, enzymes are potential therapeutic tools for treating different diseases, such as cancer, infections, and cardiovascular and cerebrovascular diseases. Precise remote enzyme activity regulation provides new opportunities to combat diseases. This review summarizes recent advances in the field of enzyme activity regulation, including reversible and irreversible regulation. It also discusses the mechanisms and approaches for on‐demand control of these activities. Furthermore, a range of stimulus‐responsive inhibitors, polymers, and nanoparticles for regulating enzyme activity and their prospective biomedical applications are summarized. Finally, the current challenges and future perspectives on enzyme activity regulation are discussed.

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“…The concept of small-molecule photo-uncaging dates back to the 1970s when cyclic adenosine monophosphate (cAMP) [ 64 ] and adenosine triphosphate (ATP) [ 65 ] were first photocaged. Since then, a wide range of small molecules including inhibitors, agonists, metabolites, and probes have been caged and successfully photo-activated in various biological systems [ 59 , 60 , 61 , 63 , 66 , 67 , 68 , 69 , 70 , 71 ]. Neurotransmitters were among the first biomolecules to be photo-uncaged to precisely control neuronal activities.…”

Section: An Overview Of Established Opto-chemical Toolsmentioning

confidence: 99%

The Development and Application of Opto-Chemical Tools in the Zebrafish

et al. 2022

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The zebrafish is one of the most widely adopted animal models in both basic and translational research. This popularity of the zebrafish results from several advantages such as a high degree of similarity to the human genome, the ease of genetic and chemical perturbations, external fertilization with high fecundity, transparent and fast-developing embryos, and relatively low cost-effective maintenance. In particular, body translucency is a unique feature of zebrafish that is not adequately obtained with other vertebrate organisms. The animal’s distinctive optical clarity and small size therefore make it a successful model for optical modulation and observation. Furthermore, the convenience of microinjection and high embryonic permeability readily allow for efficient delivery of large and small molecules into live animals. Finally, the numerous number of siblings obtained from a single pair of animals offers large replicates and improved statistical analysis of the results. In this review, we describe the development of opto-chemical tools based on various strategies that control biological activities with unprecedented spatiotemporal resolution. We also discuss the reported applications of these tools in zebrafish and highlight the current challenges and future possibilities of opto-chemical approaches, particularly at the single cell level.

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Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity

Cited by 17 publications

References 99 publications

Deactivatable Bisubstrate Inhibitors of Protein Kinases

Deactivatable Bisubstrate Inhibitors of Protein Kinases

Advanced Strategies of Enzyme Activity Regulation for Biomedical Applications

The Development and Application of Opto-Chemical Tools in the Zebrafish

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