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Cancer Cell Jul 2017Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms... (Review)
Review
Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. We discuss current challenges with the selection and use of chemical probes, and suggest how biologists can and should be more discriminating in the probes they employ.
Topics: Humans; Molecular Probes; Neoplasms; Research Design
PubMed: 28697345
DOI: 10.1016/j.ccell.2017.06.005 -
ACS Sensors Nov 2022Single-cell interrogation with the solid-state nanoprobes enables understanding of the linkage between cellular behavior and heterogeneity. Herein, inspired by the...
Single-cell interrogation with the solid-state nanoprobes enables understanding of the linkage between cellular behavior and heterogeneity. Herein, inspired by the charge property of the organic molecular probe (OMP), a generic ionic current rectification (ICR) single-cell methodology is established, exemplified by subcellular detection of glutathione (GSH) with high selectivity, sensitivity, and recyclability. The as-developed nanosensor can transduce the subcellular OMP-GSH interaction via a sensitive ionic response, which stems from the superior specificity of OMP and its essential charge property. In addition, the nanosensor exhibits good reversibility, since the subsequent tandem reaction after the recognition can well recover the sensing surface. Given the diverse structures and tailorable charge properties of OMP, this work underpins a new and general method of OMP-based ICR single-cell analysis.
Topics: Molecular Probes; Glutathione
PubMed: 36354761
DOI: 10.1021/acssensors.2c01897 -
Clinical Pharmacology and Therapeutics Nov 2018Drug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their... (Review)
Review
Drug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their potential impact to pharmacokinetic (PK) drug-drug interactions (DDIs) are an integral part of the risk assessment in drug development. To evaluate a new molecular entity as a potential perpetrator of transporters, use of well characterized and/or clinically relevant probe substrates with good selectivity and sensitivity are critical for robust clinical DDI assessment that could inform DDI management strategy in the product labeling. The availability of endogenous biomarkers to monitor transporter-mediated DDIs in early phases of clinical investigations would greatly benefit downstream clinical plans. This article reviews the state-of-the-art in transporter clinical probe drugs and emerging biomarkers, including current challenges and limitations, delineates methods and workflows to identify and validate novel endogenous biomarkers to support clinical DDI evaluations, and proposes how these probe drugs or biomarkers could be used in drug development.
Topics: Animals; Biomarkers; Drug Development; Drug Interactions; Humans; Membrane Transport Modulators; Membrane Transport Proteins; Models, Biological; Molecular Probe Techniques; Molecular Probes; Pharmacokinetics; Risk Assessment; Workflow
PubMed: 30347454
DOI: 10.1002/cpt.1216 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2022Discovery of protein-binding fragments for precisely defined binding sites is an unmet challenge to date. Herein, formylglycine is investigated as a molecular probe for...
Discovery of protein-binding fragments for precisely defined binding sites is an unmet challenge to date. Herein, formylglycine is investigated as a molecular probe for the sensitive detection of fragments binding to a spatially defined protein site . Formylglycine peptide 3 was derived from a phosphotyrosine-containing peptide substrate of protein tyrosine phosphatase PTP1B by replacing the phosphorylated amino acid with the reactive electrophile. Fragment ligation with formylglycine occurred in situ in aqueous physiological buffer. Structures and kinetics were validated by NMR spectroscopy. Screening and hit validation revealed fluorinated and non-fluorinated hit fragments being able to replace the native phosphotyrosine residue. The formylglycine probe identified low-affinity fragments with high spatial resolution as substantiated by molecular modelling. The best fragment hit, 4-amino-phenyl-acetic acid, was converted into a cellularly active, nanomolar inhibitor of the protein tyrosine phosphatase SHP2.
Topics: Acetates; Amino Acids; Binding Sites; Glycine; Molecular Probes; Peptides; Phosphotyrosine
PubMed: 35781901
DOI: 10.1002/chem.202201282 -
Molecules (Basel, Switzerland) Jan 2019A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and... (Review)
Review
A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and biological events, including cancers. Therefore, ligands interacting with G4s have attracted great attention as potential anticancer therapies or in molecular probe applications. To date, a large variety of DNA/RNA G4 ligands have been developed by a number of laboratories. As protein-targeting drugs face similar situations, G-quadruplex-interacting drugs displayed low selectivity to the targeted G-quadruplex structure. This low selectivity could cause unexpected effects that are usually reasons to halt the drug development process. In this review, we address the recent research on synthetic G4 DNA-interacting ligands that allow targeting of selected G4s as an approach toward the discovery of highly effective anticancer drugs.
Topics: Animals; Antineoplastic Agents; Binding Sites; DNA; Drug Design; G-Quadruplexes; Guanine; Humans; Ligands; Molecular Probes; Molecular Targeted Therapy; Neoplasms; Oncogenes; Structure-Activity Relationship; Telomere
PubMed: 30682877
DOI: 10.3390/molecules24030429 -
Methods in Molecular Biology (Clifton,... 2015
Topics: Coloring Agents; Molecular Probe Techniques; Molecular Probes; Proteins; Staining and Labeling
PubMed: 25710058
DOI: 10.1007/978-1-4939-2272-7 -
Current Pharmaceutical Design 2015Human serum albumin (HSA) is an abundant protein in blood and tissue fluids and has been used as a carrier for drug delivery. HSA can improve the pharmacokinetic... (Review)
Review
Human serum albumin (HSA) is an abundant protein in blood and tissue fluids and has been used as a carrier for drug delivery. HSA can improve the pharmacokinetic profiles of drugs, such as extending the blood half-life of existing drugs and reducing toxic side effects. At the same time, more and more molecular imaging probes conjugated or fused with HSA have been studied to achieve higher specificity and better pharmacokinetic performance. These molecular probes can be attached to HSA covalently or non-covalently. They can also be fused with HSA as a fusion protein or coupled with HSA in vivo. Importantly, HSA conjugated probes have been applied to many imaging modalities such as the single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), positron emission tomography (PET) and optical imaging alone or in combination with more than one modality. Besides in vivo molecular imaging, HSA conjugated probes can be used for molecular therapeutics, image-guided therapy, such as photodynamic imaging and photodynamic therapy (PDI/PDT). Some potential problems also need to be considered when using of HSA based probe strategy which are discussed in detail in the paper. Overall, HSA based probe design represents a very useful and powerful strategy for developing more molecular probes for theranostics of diseases.
Topics: Animals; Humans; Molecular Imaging; Molecular Probes; Protein Binding; Protein Structure, Secondary; Serum Albumin
PubMed: 25732549
DOI: 10.2174/1381612821666150302120517 -
ACS Sensors Oct 2022Hydrogen peroxide (HO) is a type of reactive oxygen species that regulates essential biological processes. Despite the central role of HO in pathophysiological states,...
Hydrogen peroxide (HO) is a type of reactive oxygen species that regulates essential biological processes. Despite the central role of HO in pathophysiological states, available molecular probes for assessing HO are still limited. This work develops hyperpolarized N-boronobenzyl-4-cyanopyridinium (N-BBCP) as a rationally designed molecular probe for detecting HO. The N-BBCP demonstrated favorable physicochemical and biochemical properties for HO detection and dynamic nuclear polarization, allowing noninvasive detection of HO. In particular, N-BBCP and the products possessed long spin-lattice relaxation times and spectrally resolvable N chemical shift differences. The performance of hyperpolarized N-BBCP was demonstrated both and with time-resolved N-MRS. This study highlights a promising approach to designing a reaction-based N-labeled molecular imaging agent for detecting oxidative stress
Topics: Hydrogen Peroxide; Molecular Probes; Molecular Imaging; Reactive Oxygen Species; Oxidative Stress
PubMed: 36255172
DOI: 10.1021/acssensors.2c01720 -
Molecules (Basel, Switzerland) Mar 2021Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel... (Review)
Review
Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase's biology, with wide-reaching implications for drug development.
Topics: Adenosine Triphosphate; Binding Sites; COVID-19; Casein Kinase II; Dichlororibofuranosylbenzimidazole; Humans; Molecular Probes; Naphthyridines; Phenazines; Polyphenols; Protein Kinase Inhibitors; Protein Kinases
PubMed: 33807474
DOI: 10.3390/molecules26071977 -
Current Opinion in Chemical Biology Oct 2022Membrane biology studies have revealed that in addition to providing structural support for compartment formation and membrane protein function, subcellular biomembranes... (Review)
Review
Membrane biology studies have revealed that in addition to providing structural support for compartment formation and membrane protein function, subcellular biomembranes are also critically involved in many biological events. To facilitate our understanding of the functions, biophysical properties and structural dynamics of organelle membranes, various exciting chemical biology tools have recently emerged. This short review aims to describe the latest molecular probes for organelle membrane studies. In particular, we will feature chemical strategies to visualize and quantitatively analyze the dynamic propeties of organelle membranes and lipids and discuss current limitations and potential future directions of this challenging research area.
Topics: Biology; Lipids; Membrane Proteins; Molecular Probes; Organelles
PubMed: 35779350
DOI: 10.1016/j.cbpa.2022.102182