Light‐Wavelength‐Based Quantitative Control of Dihydrofolate Reductase Activity by Using a Photochromic Isostere of an Inhibitor

  title={Light‐Wavelength‐Based Quantitative Control of Dihydrofolate Reductase Activity by Using a Photochromic Isostere of an Inhibitor},
  author={Takato Mashita and Toshiyuki Kowada and Hiroto Takahashi and Toshitaka Matsui and Shin Mizukami},
Photopharmacology has attracted research attention as a new tool for achieving optical control of biomolecules, following the methods of caged compounds and optogenetics. We have developed an efficient photopharmacological inhibitor—azoMTX—for Escherichia coli dihydrofolate reductase (eDHFR) by replacing some atoms of the original ligand, methotrexate, to achieve photoisomerization properties. This fine molecular design enabled quick structural conversion between the active “bent” Z isomer of… 
6 Citations

Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity.

This work highlights the recent progress made towards the development of light‐responsive small molecule inhibitors of selected enzymatic targets using light, given the size of this field and literature from 2015 onwards.

Comparative EPR Study on the Scavenging Effect of Methotrexate with the Isomers of Its Photoswitchable Derivative

Findings imply that trans-PHX may have more pronounced anti-inflammatory and tissue-protective effects than MTX, despite the lack of its cytotoxic, antineoplastic effect.

Weak Interactions of the Isomers of Phototrexate and Two Cavitand Derivatives

Results show opposite temperature dependence of complex stabilities, which can support the therapeutic application of the photoswitchable phototrexate, because the formation of inclusion complexes is a promising method to regulate the pharmacokinetics of drug molecules.

"Photo-Rimonabant": Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar "Cis-On" CB1R Antagonist.

It is established that 16a is highly selective for hCB1R over hCB2R, which can be valuable molecular tools for optical modulation of CBRs and better understanding of disorders associated with the endocannabinoid system.

Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors.

This systematic study critically evaluated different structure-based approaches for photopharmacology with Escherichia coli dihydrofolate reductase as a case study and identified three inhibitors that could be activated upon irradiation and reached potencies in the low-nanomolar range.



Photocontrol of Antibacterial Activity: Shifting from UV to Red Light Activation

This work introduces antibacterial agents whose activity can be controlled by visible light, while getting into the therapeutic window, and reveals an at least 8-fold difference in activity before and after irradiation with red light at 652 nm, showcasing the effective “activation” of a biological agent otherwise inactive within the investigated concentration range.

Synthesis, Characterization, and Bioactivity of the Photoisomerizable Tubulin Polymerization Inhibitor azo-Combretastatin A4.

A novel synthesis, the facile isomerization with commercial grade equipment, and biological activity of azo-combretastatin A4 in vitro and in human cancer cells are reported.

Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy.

Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form.

Photopharmacology: beyond proof of principle.

This Perspective presents the reader with the current state and outlook on photopharmacology, in particular the principles behind photoregulation of bioactivity, the challenges of molecular design, and the possible therapeutic scenarios are discussed.

Emerging Targets in Photopharmacology.

A critical overview of the different pharmacological targets in various organs and a survey of organ systems in the human body that can be addressed in a non-invasive manner are presented.

Wavelength-selective cleavage of photoprotecting groups: strategies and applications in dynamic systems.

This tutorial review discusses the design principles for dynamic systems involving wavelength-selective deprotection of photoprotecting groups, focusing on the choice and optimization of PPGs, synthetic methods for their introduction and strategies for combining multiple P PGs into one system.

Optical control of acetylcholinesterase with a tacrine switch.

One of the compounds, AzoTHA, is a reversible photochromic blocker of AChE in’vitro and ex vivo with high affinity and fast kinetics and can be used to control synaptic transmission on the neuromuscular endplate based on the light-dependent clearance of a neurotransmitter.

Inhibitor binding analysis of dihydrofolate reductases from various species.

Dihydrofolate reductases have been purified approximately 100-fold from Escherichia coil, Staphylococcus aureus, and Proteus vulgaris and to a lesser degree from rat, rabbitr guinea pig, and human

In Vivo Photopharmacology.

An overview of photopharmacology using synthetic switches that have been applied in vivo, i.e., in living cells and organisms is provided.

Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors

This work considers the first reported photoswitchable small-molecule kinase inhibitor based on azo-functionalized pyrazolopyrimidines to be a significant step forward in the development of tools for kinase signal transduction studies with spatiotemporal control over inhibitor concentration in situ.