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Current Opinion in Chemical Biology Feb 2015MicroRNAs (miRNAs) are small, non-coding RNAs that control protein expression. Aberrant miRNA expression has been linked to various human diseases, and thus miRNAs have... (Review)
Review
MicroRNAs (miRNAs) are small, non-coding RNAs that control protein expression. Aberrant miRNA expression has been linked to various human diseases, and thus miRNAs have been explored as diagnostic markers and therapeutic targets. Although it is challenging to target RNA with small molecules in general, there have been successful campaigns that have identified small molecule modulators of miRNA function by targeting various pathways. For example, small molecules that modulate transcription and target nuclease processing sites in miRNA precursors have been identified. Herein, we describe challenges in developing chemical probes that target miRNAs and highlight aspects of miRNA cellular biology elucidated by using small molecule chemical probes. We expect that this area will expand dramatically in the near future as progress is made in understanding small molecule recognition of RNA.
Topics: Animals; Base Sequence; Drug Discovery; Humans; MicroRNAs; Molecular Probe Techniques; Molecular Probes; Molecular Sequence Data; Small Molecule Libraries; Transcriptional Activation
PubMed: 25500006
DOI: 10.1016/j.cbpa.2014.10.024 -
Small (Weinheim An Der Bergstrasse,... May 2015Aptamers are composed of short RNA or single-stranded DNA sequences that, when folded into their unique 3D conformation, can bind to their targets with high specificity... (Review)
Review
Aptamers are composed of short RNA or single-stranded DNA sequences that, when folded into their unique 3D conformation, can bind to their targets with high specificity and affinity. Although functionally similar to protein antibodies, oligonucleotide aptamers offer several advantages over protein antibodies in biomedical and clinical applications. Through the enhanced permeability and retention effect, nanomedicines can improve the therapeutic index of a treatment and reduce side effects by enhancing accumulation at the disease site. However, this targets tumors passively and, thus, may not be ideal for targeted therapy. To construct ligand-directed "active targeting" nanobased delivery systems, aptamer-equipped nanomedicines have been tested for in vitro diagnosis, in vivo imaging, targeted cancer therapy, theranostic approaches, sub-cellular molecule detection, food safety, and environmental monitoring. This review focuses on the development of aptamer-conjugated nanomedicines and their application for in vivo imaging, targeted therapy, and theranostics.
Topics: Aptamers, Nucleotide; Drug Delivery Systems; Humans; Nanomedicine; Theranostic Nanomedicine
PubMed: 25677591
DOI: 10.1002/smll.201403073 -
Cell Chemical Biology Feb 2018A causal relationship between target activity modulation by small molecules and phenotypic consequence is the cornerstone of chemical biology and drug discovery. Here we... (Review)
Review
A causal relationship between target activity modulation by small molecules and phenotypic consequence is the cornerstone of chemical biology and drug discovery. Here we articulate elements of translational chemical biology, as guideposts to ensure the appropriate use of chemical probes and the conclusions drawn from cellular studies with these molecules.
Topics: Drug Discovery; Humans; Molecular Probes; Protein Processing, Post-Translational; Proteins; Small Molecule Libraries
PubMed: 29233521
DOI: 10.1016/j.chembiol.2017.11.003 -
Theranostics 2019With further research into the molecular mechanisms and roles linking immune suppression and restraint of (pre)malignancies, immunotherapies have revolutionized clinical... (Review)
Review
With further research into the molecular mechanisms and roles linking immune suppression and restraint of (pre)malignancies, immunotherapies have revolutionized clinical strategies in the treatment of cancer. However, nearly 70% of patients who received immune checkpoint therapeutics showed no response. Complementary and/or synergistic effects may occur when extracellular checkpoint antibody blockades combine with small molecules targeting intracellular signal pathways up/downstream of immune checkpoints or regulating the innate and adaptive immune response. After radiolabeling with radionuclides, small molecules can also be used for estimating treatment efficacy of immune checkpoint blockades. This review not only highlights some significant intracellular pathways and immune-related targets such as the kynurenine pathway, purinergic signaling, the kinase signaling axis, chemokines, etc., but also summarizes some attractive and potentially immunosuppression-related small molecule agents, which may be synergistic with extracellular immune checkpoint blockade. In addition, opportunities for small molecule-based theranostics in cancer immunology will be discussed.
Topics: Animals; Humans; Immune System; Immunotherapy; Neoplasms; Small Molecule Libraries; Theranostic Nanomedicine
PubMed: 31695804
DOI: 10.7150/thno.37218 -
Methods in Enzymology 2019Understanding how to design small molecules that target coding and non-coding RNA has the potential to exponentially increase the number of therapeutically-relevant...
Understanding how to design small molecules that target coding and non-coding RNA has the potential to exponentially increase the number of therapeutically-relevant druggable targets, which are currently mostly proteins. However, there is limited information on the principles at the basis of RNA recognition. In this chapter, we describe a pattern-based technique that can be used for the simultaneous elucidation of RNA motifs and small molecule features for RNA selective recognition, termed Pattern Recognition of RNA by Small Molecules (PRRSM). We provide protocols for the computational design and synthetic preparation of an RNA training set as well as how to perform the assay in plate reader format. Furthermore, we provide details on how to perform and interpret the statistical analysis and indicate possible future extensions of the technique. By combining insights into characteristics of the small molecules and of the RNA that leads to differentiation, PRRSM promises to accelerate the elucidation of the determinants at the basis of RNA recognition.
Topics: Aminoglycosides; Fluorescent Dyes; Guanidine; Nucleic Acid Conformation; Nucleotide Motifs; Organophosphorus Compounds; Principal Component Analysis; RNA; Small Molecule Libraries; Software; Spectrometry, Fluorescence
PubMed: 31239043
DOI: 10.1016/bs.mie.2019.05.022 -
PloS One 2021The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency of international concern. The spike glycoprotein (S protein) of...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency of international concern. The spike glycoprotein (S protein) of SARS-CoV-2 is a key target of antiviral drugs. Focusing on the existing S protein structure, molecular docking was used in this study to calculate the binding energy and interaction sites between 14 antiviral molecules with different structures and the SARS-CoV-2 S protein, and the potential drug candidates targeting the SARS-CoV-2 S protein were analyzed. Tizoxanide, dolutegravir, bictegravir, and arbidol were found to have high binding energies, and they effectively bind key sites of the S1 and S2 subunits, inhibiting the virus by causing conformational changes in S1 and S2 during the fusion of the S protein with host cells. Based on the interactions among the drug molecules, the S protein and the amino acid environment around the binding sites, rational structure-based optimization was performed using the molecular connection method and bioisosterism strategy to obtain Ti-2, BD-2, and Ar-3, which have much stronger binding ability to the S protein than the original molecules. This study provides valuable clues for identifying S protein inhibitor binding sites and the mechanism of the anti-SARS-CoV-2 effect as well as useful inspiration and help for the discovery and optimization of small molecule S protein inhibitors.
Topics: Antiviral Agents; COVID-19; Drug Design; Drug Discovery; Humans; Molecular Docking Simulation; SARS-CoV-2; Small Molecule Libraries; Spike Glycoprotein, Coronavirus; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33493227
DOI: 10.1371/journal.pone.0245975 -
Molecules (Basel, Switzerland) Mar 2022Tumor differentiation is a therapeutic strategy aimed at reactivating the endogenous differentiation program of cancer cells and inducing cancer cells to mature and... (Review)
Review
Tumor differentiation is a therapeutic strategy aimed at reactivating the endogenous differentiation program of cancer cells and inducing cancer cells to mature and differentiate into other types of cells. It has been found that a variety of natural small-molecule drugs can induce tumor cell differentiation both in vitro and in vivo. Relevant molecules involved in the differentiation process may be potential therapeutic targets for tumor cells. Compared with synthetic drugs, natural small-molecule antitumor compounds have the characteristics of wide sources, structural diversity and low toxicity. In addition, natural drugs with structural modification and transformation have relatively concentrated targets and enhanced efficacy. Therefore, using natural small-molecule compounds to induce malignant cell differentiation represents a more targeted and potential low-toxicity means of tumor treatment. In this review, we focus on natural small-molecule compounds that induce differentiation of myeloid leukemia cells, osteoblasts and other malignant cells into functional cells by regulating signaling pathways and the expression of specific genes. We provide a reference for the subsequent development of natural small molecules for antitumor applications and promote the development of differentiation therapy.
Topics: Cell Differentiation; Humans; Leukemia, Myeloid; Neoplasms; Signal Transduction
PubMed: 35408534
DOI: 10.3390/molecules27072128 -
Journal of Visualized Experiments : JoVE Mar 2021A detailed protocol for preparing small molecule samples for microcrystal electron diffraction (MicroED) experiments is described. MicroED has been developed to solve...
A detailed protocol for preparing small molecule samples for microcrystal electron diffraction (MicroED) experiments is described. MicroED has been developed to solve structures of proteins and small molecules using standard electron cryo-microscopy (cryo-EM) equipment. In this way, small molecules, peptides, soluble proteins, and membrane proteins have recently been determined to high resolutions. Protocols are presented here for preparing grids of small-molecule pharmaceuticals using the drug carbamazepine as an example. Protocols for screening and collecting data are presented. Additional steps in the overall process, such as data integration, structure determination, and refinement are presented elsewhere. The time required to prepare the small-molecule grids is estimated to be less than 30 min.
Topics: Cryoelectron Microscopy; Electrons
PubMed: 33779618
DOI: 10.3791/62313 -
Biophysical Journal Mar 2019Single-molecule and super-resolution imaging relies on successful, sensitive, and accurate detection of the emission from fluorescent molecules. Yet, despite the...
Single-molecule and super-resolution imaging relies on successful, sensitive, and accurate detection of the emission from fluorescent molecules. Yet, despite the widespread adoption of super-resolution microscopies, single-molecule data processing algorithms can fail to provide accurate measurements of the brightness and position of molecules in the presence of backgrounds that fluctuate significantly over time and space. Thus, samples or experiments that include obscuring backgrounds can severely, or even completely, hinder this process. To date, no general data analysis approach to this problem has been introduced that is capable of removing obscuring backgrounds for a wide variety of experimental modalities. To address this need, we present the Single-Molecule Accurate LocaLization by LocAl Background Subtraction (SMALL-LABS) algorithm, which can be incorporated into existing single-molecule and super-resolution analysis packages to accurately locate and measure the intensity of single molecules, regardless of the shape or brightness of the background. Accurate background subtraction is enabled by separating the foreground from the background based on differences in the temporal variations of the foreground and the background (i.e., fluorophore blinking, bleaching, or moving). We detail the function of SMALL-LABS here, and we validate the SMALL-LABS algorithm on simulated data as well as real data from single-molecule imaging in living cells.
Topics: Bacillus subtilis; Cell Survival; Single Molecule Imaging
PubMed: 30846363
DOI: 10.1016/j.bpj.2019.02.006 -
Cell Chemical Biology Feb 2022MicroRNA families are ubiquitous in the human transcriptome, yet targeting of individual members is challenging because of sequence homology. Many secondary structures...
MicroRNA families are ubiquitous in the human transcriptome, yet targeting of individual members is challenging because of sequence homology. Many secondary structures of the precursors to these miRNAs (pri- and pre-miRNAs), however, are quite different. Here, we demonstrate both in vitro and in cellulis that design of structure-specific small molecules can inhibit a particular miRNA family member to modulate a disease pathway. The miR-200 family consists of five miRNAs, miR-200a, -200b, -200c, -141, and -429, and is associated with type 2 diabetes (T2D). We designed a small molecule that potently and selectively targets pre-miR-200c's structure and reverses a pro-apoptotic effect in a pancreatic β cell model. In contrast, an oligonucleotide targeting the RNA's sequence inhibited all family members. Global proteomics and RNA sequencing analyses further demonstrate selectivity for miR-200c. Collectively, these studies establish that miR-200c plays an important role in T2D, and small molecules targeting RNA structure can be an important complement to oligonucleotides.
Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Insulin-Secreting Cells; Ligands; Mice; MicroRNAs; Phenotype; Sequence Analysis, RNA; Small Molecule Libraries
PubMed: 34320373
DOI: 10.1016/j.chembiol.2021.07.006