Rational Design in Photopharmacology with Molecular Photoswitches

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(30)

Published: April 7, 2023

Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into structure biologically active small molecules to allow optical control their potency. Going beyond trial and error, photopharmacology has progressively applied rational design methodologies devise light-controlled bioactive ligands. this review, we categorize photopharmacological efforts from standpoint medicinal chemistry strategies, focusing on diffusible photochromic ligands modified that operate through E-Z bond isomerization. vast majority cases, photoswitchable designed as analogs existing compounds, a variety approaches. By analyzing in detail comprehensive list instructive examples, describe state art discuss future opportunities photopharmacology.

Language: Английский

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New Molecular Photoswitch Based on the Conformational Transition of Phenothiazine Derivatives and Corresponding Triplet Emission Properties

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Molecular photoswitch research has drawn much attention in the last century owing to its great potential development of smart materials. However, photoswitches suitable for constructing light-responsive luminescent materials remain limited, especially those involving triplet-state phosphorescence. Herein, we designed a novel molecular based on conformation transition phenothiazine derivatives, minimizing steric hindrance (-CH

Language: Английский

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Photocontrol of the β-Hairpin Polypeptide Structure through an Optimized Azobenzene-Based Amino Acid Analogue

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(3), P. 2062 - 2071

Published: Jan. 16, 2024

A family of neurodegenerative diseases, including Huntington's disease (HD) and spinocerebellar ataxias, are associated with an abnormal polyglutamine (polyQ) expansion in mutant proteins that become prone to form amyloid-like aggregates. Prior studies have suggested a key role for β-hairpin formation as driver nucleation aggregation, but direct experimental been challenging. Toward such research, we set out enable spatiotemporal control over by the introduction photosensitive β-turn mimic polypeptide backbone, consisting newly designed azobenzene derivative. The reported derivative overcomes limitations prior approaches poor photochemical properties imperfect structural compatibility desired structure. new azobenzene-based was designed, synthesized, found display improved properties, both after incorporation into backbone polyQ polypeptide. two isomers azobenzene-polyQ peptide showed different aggregate structures fibrils, demonstrated electron microscopy solid-state NMR (ssNMR). Notably, only peptides which structure stabilized (azobenzene cis configuration) closely reproduced spectral fingerprints toxic, β-hairpin-containing fibrils formed huntingtin protein fragments implicated HD. These findings will better deciphering roles aggregation processes HD other amyloid-related diseases.

Language: Английский

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Comprehensive review of amino acid transporters as therapeutic targets

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 260, P. 129646 - 129646

Published: Jan. 23, 2024

Language: Английский

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Direct Growth Control of Antibiotic‐Resistant Bacteria Using Visible‐Light‐Responsive Novel Photoswitchable Antibiotics

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(15)

Published: Jan. 13, 2024

Abstract In addition to the discovery of new (modified) potent antibiotics combat antibiotic resistance, there is a critical need develop novel strategies that would restrict their off‐target effects and unnecessary exposure bacteria in our body environment. We report set photoswitchable arylazopyrazole‐modified norfloxacin present high degree bidirectional photoisomerization, impressive fatigue resistance reasonably cis half‐lives. The irradiated isomers most compounds were found exhibit nearly equal or higher antibacterial activity than against Gram‐positive bacteria. Notably, norfloxacin‐resistant S. aureus bacteria, visible‐light‐responsive p ‐SMe‐substituted derivative showed remarkably antimicrobial potency (MIC 0.25 μg/mL) state, while was reduced by 24‐fold case its non‐irradiated state. estimated be retained for more 7 hours. This first demonstrate direct photochemical control growth antibiotic‐resistant show highest difference between states antibiotic. Additionally, both non‐harmful human cells. Molecular modellings performed identify underlying reason behind high‐affinity binding isomer topoisomerase IV enzyme.

Language: Английский

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Controlling the Covalent Reactivity of a Kinase Inhibitor with Light

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(37), P. 20178 - 20183

Published: June 3, 2021

Covalent kinase inhibitors account for some of the most successful drugs that have recently entered clinic and many others are in preclinical development. A common strategy is to target cysteines vicinity ATP binding site using an acrylamide electrophile. To increase tissue selectivity inhibitors, it could be advantageous control reactivity these electrophiles with light. Here, we introduce covalent JNK3 function as photoswitchable affinity labels (PALs). Our lead compounds contain a diazocine photoswitch, poor non-covalent dark, become effective after irradiation visible proposed mode action supported by X-ray structures explain why unreactive dark undergo proximity-based attachment following exposure

Language: Английский

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Optical control of Class A G protein-coupled receptors with photoswitchable ligands

Current Opinion in Pharmacology, Journal Year: 2022, Volume and Issue: 63, P. 102192 - 102192

Published: March 4, 2022

The field of photopharmacology Class A GPCR ligands has recently attracted attention. In this review we analyze 31 papers on currently available photoswitchable for GPCRs. Using the six most recurring terms all combined paper abstracts, one can extract overarching goal area research: "Photoswitchable control receptor activity with light" (represented in TOC graphic). We design, photochemistry and pharmacology ligands. Trends, challenges limitations will be discussed. number efficient that allow optical modulation function various vitro assays are presented. Moreover, vivo is within reach first reports to end highlighted.

Language: Английский

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Structural basis of ligand binding modes of human EAAT2

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: June 9, 2022

Abstract In the central nervous system (CNS), excitatory amino acid transporters (EAATs) mediate uptake of neurotransmitter glutamate and maintain its low concentrations in synaptic cleft for avoiding neuronal cytotoxicity. Dysfunction EAATs can lead to many psychiatric diseases. Here we report cryo-EM structures human EAAT2 an inward-facing conformation, presence substrate or selective inhibitor WAY-213613. The is coordinated by extensive hydrogen bonds further stabilized HP2. WAY-213613 occupies a similar binding pocket that glutamate. Upon association with WAY-213613, HP2 undergoes substantial conformational change, turn stabilizes forming hydrophobic interactions. Electrophysiological experiments elucidate unique S441 plays pivotal roles hEAAT2 I464-L467-V468 cluster acts as key structural determinant inhibition this transporter

Language: Английский

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Responsive Nanostructure for Targeted Drug Delivery

Journal of Nanotheranostics, Journal Year: 2023, Volume and Issue: 4(1), P. 55 - 85

Published: Feb. 8, 2023

Currently, intelligent, responsive biomaterials have been widely explored, considering the fact that provide controlled and predictable results in various biomedical systems. Responsive nanostructures undergo reversible or irreversible changes presence of a stimulus, stimuli can be temperature, magnetic field, ultrasound, pH, humidity, pressure, light, electric etc. Different types being used drug delivery shall explained here. Recent research progress design, development applications comprising is also described More emphasis will given on explored for smart at target site such as wound healing, cancer therapy, inflammation, pain management order to achieve improved efficacy sustainability with lowest side effects. However, it still big challenge develop well-defined ordered output; thus, challenges faced during design these included this article. Clinical perspectives applicability targeted discussed

Language: Английский

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Rational Design in Photopharmacology with Molecular Photoswitches

Angewandte Chemie, Journal Year: 2023, Volume and Issue: 135(30)

Published: April 7, 2023

Abstract Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into structure biologically active small molecules to allow optical control their potency. Going beyond trial and error, photopharmacology has progressively applied rational design methodologies devise light‐controlled bioactive ligands. this review, we categorize photopharmacological efforts from standpoint medicinal chemistry strategies, focusing on diffusible photochromic ligands modified that operate through E‐Z bond isomerization. vast majority cases, photoswitchable designed as analogs existing compounds, a variety approaches. By analyzing in detail comprehensive list instructive examples, describe state art discuss future opportunities photopharmacology.

Language: Английский

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