Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands.

Anesth Analg

From the Departments of *Anesthesiology and Critical Care and †Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; ‡Department of Chemistry, University of Pennsylvania School of Arts and Sciences, Philadelphia, Pennsylvania; and §Department of Physics, Rutgers University, Camden, New Jersey.

Published: November 2016

Anesthetic photoaffinity ligands have had an increasing presence within anesthesiology research. These ligands mimic parent general anesthetics and allow investigators to study anesthetic interactions with receptors and enzymes; identify novel targets; and determine distribution within biological systems. To date, nearly all general anesthetics used in medicine have a corresponding photoaffinity ligand represented in the literature. In this review, we examine all aspects of the current methodologies, including ligand design, characterization, and deployment. Finally we offer points of consideration and highlight the future outlook as more photoaffinity ligands emerge within the field.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072990PMC
http://dx.doi.org/10.1213/ANE.0000000000001365DOI Listing

Publication Analysis

Top Keywords

photoaffinity ligands
12
general anesthetics
8
shedding light
4
light anesthetic
4
anesthetic mechanisms
4
mechanisms application
4
photoaffinity
4
application photoaffinity
4
ligands
4
ligands anesthetic
4

Similar Publications

The outer mitochondrial membrane protein known as mitoNEET was discovered when it was labeled by a photoaffinity derivative of the anti-diabetes medication, pioglitazone. The biological role for mitoNEET and its specific mechanism for achieving this remains an active subject for research. There is accumulating evidence suggesting that mitoNEET could be a component of mitochondrial FeS cofactor biogenesis.

View Article and Find Full Text PDF

Identification and validation of WDR5 WIN-site ligands via DNA-encoded chemical library screening.

Bioorg Chem

January 2025

Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, PR China; Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou 310058, PR China. Electronic address:

WD repeat-containing protein 5 (WDR5) is a scaffolding protein involved in critical protein-protein interactions and a promising target for therapeutic development. Novel small-molecule ligands targeting WDR5 were identified using the DELopen platform, a free-access DNA-encoded chemical library (DEL) for academic research. Through off-DNA structure-activity relationship studies and photoaffinity labeling, two promising initial leads, DBL-6-13 and DBL-6-33, were identified as new binders of WDR5.

View Article and Find Full Text PDF

Mutations in creatine transporter SLC6A8 cause creatine transporter deficiency (CTD), which is responsible for 2% of all cases of X-linked intellectual disability. CTD has no current treatments and has a high unmet medical need. Inspired by the transformational therapeutic impact of small molecule "correctors" for the treatment of cystic fibrosis, which bind to mutated versions of the CFTR ion channel to promote its trafficking to the cell surface, we sought to identify small molecules that could stabilize SLC6A8 as a potential treatment for CTD.

View Article and Find Full Text PDF

End-to-End Throughput Chemical Proteomics for Photoaffinity Labeling Target Engagement and Deconvolution.

J Proteome Res

November 2024

Janssen Research & Development, LLC, 301 Binney Street, Cambridge, Massachusetts 02142, United States.

Photoaffinity labeling (PAL) methodologies have proven to be instrumental for the unbiased deconvolution of protein-ligand binding events in physiologically relevant systems. However, like other chemical proteomic workflows, they are limited in many ways by time-intensive sample manipulations and data acquisition techniques. Here, we describe an approach to address this challenge through the innovation of a carboxylate bead-based protein cleanup procedure to remove excess small-molecule contaminants and couple it to plate-based, proteomic sample processing as a semiautomated solution.

View Article and Find Full Text PDF

Current methods for proteomimetic engineering rely on structure-based design. Here we describe a design strategy that allows the construction of proteomimetics against challenging targets without a priori characterization of the target surface. Our approach employs (i) a 100-membered photoreactive foldamer library, the members of which act as local surface mimetics, and (ii) the subsequent affinity maturation of the primary hits using systems chemistry.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!