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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 -
Trends in Analytical Chemistry : TRAC Dec 2019Aptamers are nucleic acid-based affinity reagents that have gained widespread attention as biorecognition elements for the detection of targets such as ions, small...
Aptamers are nucleic acid-based affinity reagents that have gained widespread attention as biorecognition elements for the detection of targets such as ions, small molecules, and proteins. Over the past three decades, the field of aptamer-based sensing has grown considerably. However, the advancement of aptamer-based small-molecule detection has fallen short of the high demand for such sensors in applications such as diagnostics, environmental monitoring, and forensics. This is due to two challenges: the complexity of developing generalized sensing platforms and the poor sensitivities of assays targeting small molecules. This paper will review new approaches for the streamlined development of high-performance aptamer-based sensors for small-molecule detection. We here provide historical context, explore the current state-of-the art, and offer future directions-with emphasis placed on new aptamer engineering methods, the use of cooperative binding, and label-free approaches using fully-folded, high-affinity aptamers for small-molecule sensing.
PubMed: 32863483
DOI: 10.1016/j.trac.2019.115699 -
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 -
Biomacromolecules Apr 2019Binding of small molecules to mucus membranes in the body has an important role in human health, as it can affect the diffusivity and activity of any molecule that acts...
Binding of small molecules to mucus membranes in the body has an important role in human health, as it can affect the diffusivity and activity of any molecule that acts in a mucosal environment. The binding of drugs and of toxins and signaling molecules from mucosal pathogens is of particular clinical interest. Despite the importance of mucus-small molecule binding, there is a lack of data revealing the precise chemical features of small molecules that lead to mucus binding. We developed a novel equilibrium dialysis assay to measure the binding of libraries of small molecules to mucin and other mucus components, substantially increasing the throughput of small molecule binding measurements. We validated the biological relevance of our approach by quantifying binding of the antibiotic colistin to mucin, and showing that this binding was associated with inhibition of colistin's bioactivity. We next used a small molecule microarray to identify 2,4-diaminopyrimidine as a mucin binding motif and confirmed the importance of this motif for mucin binding using equilibrium dialysis. Furthermore, we showed that, for molecules with this motif, binding to mucins and the mucus-associated biopolymers DNA and alginate is modulated by differences in hydrophobicity and charge. Finally, we showed that molecules lacking the motif exhibited different binding trends from those containing the motif. These results open up the prospect of routine testing of small molecule binding to mucus and optimization of drugs for clinically relevant mucus binding properties.
Topics: Amino Acid Motifs; Animals; DNA; Humans; Hydrophobic and Hydrophilic Interactions; Mucins; Mucous Membrane
PubMed: 30779551
DOI: 10.1021/acs.biomac.8b01467 -
Molecules (Basel, Switzerland) Dec 2020The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have... (Review)
Review
The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.
Topics: Hydrophobic and Hydrophilic Interactions; Models, Molecular; Protein Binding; Small Molecule Libraries; Transcription Factors
PubMed: 33352993
DOI: 10.3390/molecules25246001 -
Chembiochem : a European Journal of... Jan 2015Next-generation-sequencing (NGS) technologies enable us to obtain extensive information by deciphering millions of individual DNA sequencing reactions simultaneously.... (Review)
Review
Next-generation-sequencing (NGS) technologies enable us to obtain extensive information by deciphering millions of individual DNA sequencing reactions simultaneously. The new DNA-sequencing strategies exceed their precursors in output by many orders of magnitude, resulting in a quantitative increase in valuable sequence information that could be harnessed for qualitative analysis. Sequencing on this scale has facilitated significant advances in diverse disciplines, ranging from the discovery, design, and evaluation of many small molecules and relevant biological mechanisms to maturation of personalized therapies. NGS technologies that have recently become affordable allow us to gain in-depth insight into small-molecule-triggered biological phenomena and empower researchers to develop advanced versions of small molecules. In this review we focus on the overlooked implications of NGS technologies in chemical biology, with a special emphasis on small-molecule development and screening.
Topics: Biochemistry; Computational Biology; Drug Discovery; Genome, Human; High-Throughput Nucleotide Sequencing; High-Throughput Screening Assays; Humans; Nucleic Acid Conformation; Precision Medicine; Small Molecule Libraries
PubMed: 25421391
DOI: 10.1002/cbic.201402556 -
Journal of Personalized Medicine Jan 2024The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone in the fight against... (Review)
Review
The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone in the fight against malignancies. However, the majority of clinically employed immune checkpoint inhibitors are monoclonal antibodies (mAbs) with several limitations, such as poor oral bioavailability and immune-related adverse effects (irAEs). Another major limitation is the restriction of the efficacy of mAbs to a subset of cancer patients, which triggered extensive research efforts to identify alternative approaches in targeting immune checkpoints aiming to overcome the restricted efficacy of mAbs. This comprehensive review aims to explore the cutting-edge developments in targeting immune checkpoints, focusing on both small molecule- and peptide-based approaches. By delving into drug discovery platforms, we provide insights into the diverse strategies employed to identify and optimize small molecules and peptides as inhibitors of immune checkpoints. In addition, we discuss recent advances in nanomaterials as drug carriers, providing a basis for the development of small molecule- and peptide-based platforms for cancer immunotherapy. Ongoing research focused on the discovery of small molecules and peptide-inspired agents targeting immune checkpoints paves the way for developing orally bioavailable agents as the next-generation cancer immunotherapies.
PubMed: 38248769
DOI: 10.3390/jpm14010068 -
Current Opinion in Plant Biology Aug 2023Biomolecular condensate (BMCs) formation facilitates the grouping of molecules, including proteins, nucleic acids, and small molecules, creating specific... (Review)
Review
Biomolecular condensate (BMCs) formation facilitates the grouping of molecules, including proteins, nucleic acids, and small molecules, creating specific microenvironments with particular functions. They are often assembled through liquid-liquid phase separation (LLPS), a phenomenon that arises when specific proteins, nucleic acids, and small molecules demix from the aqueous environment into another phase with different physiochemical properties. BMCs assemble and disassemble in response to external and internal stimuli such as temperature, molecule concentration, ionic strength, pH, and cellular redox state. Likewise, the nature of the regulatory stimuli may affect the lifespan, morphology, and content of BMCs. In humans, compelling evidence points to the critical role of BMCs in diseases. By contrast, the link between BMC formation, stress resistance, and cell survival has not been revealed in plants. Recent studies have pointed out the nascent roles of small molecules in the assembly and dynamics of BMCs; however, this is still an emerging field of study. This review briefly highlights the most significant efforts to identify the molecular mechanisms between small molecules and BMC formation and regulation in plants and other organisms. We then discuss (i) how small molecules exert control over the BMC assembly and dynamics in plants and (ii) how small molecules can influence the formation and material properties of plant BMCs. Finally, we propose novel alternatives that might help to understand the relationship between chemicals and condensation dynamics and their possible application to plant biotechnology.
Topics: Humans; Biomolecular Condensates; Nucleic Acids
PubMed: 37348448
DOI: 10.1016/j.pbi.2023.102385 -
Wiley Interdisciplinary Reviews. RNA Jul 2018The recognition of RNA functions beyond canonical protein synthesis has challenged the central dogma of molecular biology. Indeed, RNA is now known to directly regulate... (Review)
Review
The recognition of RNA functions beyond canonical protein synthesis has challenged the central dogma of molecular biology. Indeed, RNA is now known to directly regulate many important cellular processes, including transcription, splicing, translation, and epigenetic modifications. The misregulation of these processes in disease has led to an appreciation of RNA as a therapeutic target. This potential was first recognized in bacteria and viruses, but discoveries of new RNA classes following the sequencing of the human genome have invigorated exploration of its disease-related functions in mammals. As stable structure formation is evolving as a hallmark of mammalian RNAs, the prospect of utilizing small molecules to specifically probe the function of RNA structural domains and their interactions is gaining increased recognition. To date, researchers have discovered bioactive small molecules that modulate phenotypes by binding to expanded repeats, microRNAs, G-quadruplex structures, and RNA splice sites in neurological disorders, cancers, and other diseases. The lessons learned from achieving these successes both call for additional studies and encourage exploration of the plethora of mammalian RNAs whose precise mechanisms of action remain to be elucidated. Efforts toward understanding fundamental principles of small molecule-RNA recognition combined with advances in methodology development should pave the way toward targeting emerging RNA classes such as long noncoding RNAs. Together, these endeavors can unlock the full potential of small molecule-based probing of RNA-regulated processes and enable us to discover new biology and underexplored avenues for therapeutic intervention in human disease. This article is categorized under: RNA Methods > RNA Analyses In Vitro and In Silico RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions RNA in Disease and Development > RNA in Disease.
Topics: Animals; Humans; Neoplasms; Nervous System Diseases; Phenotype; RNA; RNA Probes; RNA Splice Sites; Small Molecule Libraries
PubMed: 29726113
DOI: 10.1002/wrna.1477 -
Chemical Society Reviews Mar 2021Recent advances in our understanding of RNA biology have uncovered crucial roles for RNA in multiple disease states, ranging from viral and bacterial infections to... (Review)
Review
Recent advances in our understanding of RNA biology have uncovered crucial roles for RNA in multiple disease states, ranging from viral and bacterial infections to cancer and neurological disorders. As a result, multiple laboratories have become interested in developing drug-like small molecules to target RNA. However, this development comes with multiple unique challenges. For example, RNA is inherently dynamic and has limited chemical diversity. In addition, promiscuous RNA-binding ligands are often identified during screening campaigns. This Tutorial Review overviews important considerations and advancements for generating RNA-targeted small molecules, ranging from fundamental chemistry to promising small molecule examples with demonstrated clinical efficacy. Specifically, we begin by exploring RNA functional classes, structural hierarchy, and dynamics. We then discuss fundamental RNA recognition principles along with methods for small molecule screening and RNA structure determination. Finally, we review unique challenges and emerging solutions from both the RNA and small molecule perspectives for generating RNA-targeted ligands before highlighting a selection of the "Greatest Hits" to date. These molecules target RNA in a variety of diseases, including cancer, neurodegeneration, and viral infection, in cellular and animal model systems. Additionally, we explore the recently FDA-approved small molecule regulator of RNA splicing, risdiplam, for treatment of spinal muscular atrophy. Together, this Tutorial Review showcases the fundamental role of chemical and molecular recognition principles in enhancing our understanding of RNA biology and contributing to the rapidly growing number of RNA-targeted probes and therapeutics. In particular, we hope this widely accessible review will serve as inspiration for aspiring small molecule and/or RNA researchers.
Topics: Animals; Base Sequence; High-Throughput Screening Assays; Humans; Ligands; Molecular Probes; Neoplasms; Nucleic Acid Conformation; RNA; Small Molecule Libraries; Virus Diseases
PubMed: 33458725
DOI: 10.1039/d0cs01261k