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Annals of the New York Academy of... Jul 2020Aberrant RNA structure and function operate in neurological disease progression and severity. As RNA contributes to disease pathology in a complex fashion, that is, via... (Review)
Review
Aberrant RNA structure and function operate in neurological disease progression and severity. As RNA contributes to disease pathology in a complex fashion, that is, via various mechanisms, it has become an attractive therapeutic target for small molecules and oligonucleotides. In this review, we discuss the identification of RNA structures that cause or contribute to neurological diseases as well as recent progress toward the development of small molecules that target them, including small molecule modulators of pre-mRNA splicing and RNA repeat expansions that cause microsatellite disorders such as Huntington's disease and amyotrophic lateral sclerosis. The use of oligonucleotide-based modalities is also discussed. There are key differences between small molecule and oligonucleotide targeting of RNA. The former targets RNA structure, while the latter prefers unstructured regions. Thus, some targets will be preferentially targeted by oligonucleotides and others by small molecules.
Topics: Amyotrophic Lateral Sclerosis; Humans; Huntington Disease; Nervous System Diseases; Nucleic Acid Conformation; Oligonucleotides; RNA; RNA Precursors; RNA Splicing; Small Molecule Libraries
PubMed: 30964958
DOI: 10.1111/nyas.14051 -
Annual Review of Pharmacology and... Jan 2017Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to... (Review)
Review
Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. First, we highlight all-small-molecule techniques with direct clinical application. Second, we describe techniques that may find broader acceptance in the biomedical research community that require little or no synthetic chemistry. In addition to serving as innovative research tools, these new approaches to control intracellular protein levels offer the potential to develop novel therapeutics targeting proteins that are not currently pharmaceutically vulnerable.
Topics: Animals; Drug Delivery Systems; Humans; Oligopeptides; Proteins; Proteolysis; Small Molecule Libraries
PubMed: 27732798
DOI: 10.1146/annurev-pharmtox-010715-103507 -
Frontiers in Bioengineering and... 2022The lack of regenerative capacity of neurons leads to poor prognoses for some neurological disorders. The use of small molecules to directly reprogram somatic cells into... (Review)
Review
The lack of regenerative capacity of neurons leads to poor prognoses for some neurological disorders. The use of small molecules to directly reprogram somatic cells into neurons provides a new therapeutic strategy for neurological diseases. In this review, the mechanisms of action of different small molecules, the approaches to screening small molecule cocktails, and the methods employed to detect their reprogramming efficiency are discussed, and the studies, focusing on neuronal reprogramming using small molecules in neurological disease models, are collected. Future research efforts are needed to investigate the mechanisms of small molecule-mediated neuronal reprogramming under pathophysiological states, optimize screening cocktails and dosing regimens, and identify safe and effective delivery routes to promote neural regeneration in different neurological diseases.
PubMed: 35875485
DOI: 10.3389/fbioe.2022.799152 -
Small (Weinheim An Der Bergstrasse,... Mar 2022Reversible electrochemical intercalation of cations into the interlayer space of 2D materials induces tunable physical and chemical properties in them. In MXenes, a...
Reversible electrochemical intercalation of cations into the interlayer space of 2D materials induces tunable physical and chemical properties in them. In MXenes, a large class of recently developed 2D carbides and nitrides, low intercalation energy, high storage capacitance, and reversible intercalation of various cations have led to their improved performance in sensing and energy storage applications. Herein, a coupled nanopore-actuator system where an ultrathin free-standing MXene film serves as a nanopore support membrane and ionically active actuator is reported. In this system, the contactless MXene membrane in the electric field affects the cation movement in the field through their (de)intercalation between individual MXene flakes. This results in reversible swelling and contraction of the membrane monitored by ionic conductance through the nanopore. This unique nanopore coupled to a mechanical actuation system could provide new insights into designing single-molecule biosensing platforms at the nanoscale.
Topics: Cations; Electric Capacitance; Electricity; Nanopores
PubMed: 35297185
DOI: 10.1002/smll.202105857 -
Journal of Biomedical Science Sep 2022Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic.... (Review)
Review
Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from numerous teams have led to the generation of a voluminous library composed of chemically and mechanistically diverse small molecules as anti-COVID19 scaffolds. This review article presents an overview of medicinal chemistry campaigns and drug repurposing programs that culminated in the identification of a plethora of small molecule-based anti-COVID19 drugs mediating their antiviral effects through inhibition of proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin and other targets. In light of the evidence ascertaining the potential of small molecule drugs to approach conserved proteins required for the viral replication of all coronaviruses, accelerated FDA approvals are anticipated for small molecules for the treatment of COVID19 shortly. Though the recent attempts invested in this direction in pursuit of enrichment of the anti-COVID-19 armoury (chemical tools) are praiseworthy, some strategies need to be implemented to extract conclusive benefits of the recently reported small molecule viz. (i) detailed preclinical investigation of the generated anti-COVID19 scaffolds (ii) in-vitro profiling of the inhibitors against the emerging SARS-CoV-2 variants (iii) development of assays enabling rapid screening of the libraries of anti-COVID19 scaffold (iv) leveraging the applications of machine learning based predictive models to expedite the anti-COVID19 drug discovery campaign (v) design of antibody-drug conjugates.
Topics: COVID-19; Humans; Pandemics; Peptides; SARS-CoV-2; Vaccines; COVID-19 Drug Treatment
PubMed: 36064696
DOI: 10.1186/s12929-022-00847-6 -
F1000Research 2019Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath... (Review)
Review
Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell-directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.
Topics: Animals; Antineoplastic Agents; B-Lymphocytes; Mice; Multiple Sclerosis; Small Molecule Libraries
PubMed: 30863536
DOI: 10.12688/f1000research.16495.1 -
Biophysical Reviews Aug 2019Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting... (Review)
Review
Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting pathophysiological cues and disease progression. Over the years, targeting intracellular PPIs as drug design targets has been a challenging task owing to their highly dynamic and expansive interfacial areas (flat, featureless and relatively large). However, advances in PPI-focused drug discovery technology have been reported and a few drugs are already on the market, with some potential drug-like candidates already in clinical trials. In this article, we review the advances, successes and remaining challenges in the application of small molecules as valuable PPI modulators in disease diagnosis and therapeutics.
PubMed: 31301019
DOI: 10.1007/s12551-019-00570-x -
Journal of Medicinal Chemistry May 2022The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases.... (Review)
Review
The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases. β-Catenin is a multifunctional protein within this pathway and an attractive yet challenging therapeutic target, most notably in oncology. This has stimulated the search for potent small-molecule inhibitors binding directly to the β-catenin surface to inhibit its protein-protein interactions and downstream signaling. Here, we provide an account of the claimed (and some putative) small-molecule ligands of β-catenin from the literature. Through in silico analysis, we show that most of these molecules contain promiscuous chemical substructures notorious for interfering with screening assays. Finally, and in line with this analysis, we demonstrate using orthogonal biophysical techniques that none of the examined small molecules bind at the surface of β-catenin. While shedding doubts on their reported mode of action, this study also reaffirms β-catenin as a prominent target in drug discovery.
Topics: Animals; Biophysical Phenomena; Drug Discovery; Humans; Small Molecule Libraries; Wnt Signaling Pathway; beta Catenin
PubMed: 35581674
DOI: 10.1021/acs.jmedchem.2c00228 -
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 -
Regulatory Toxicology and Pharmacology... Jul 2022Therapies have been developed in the last couple of years to allow vaccination against, or treatment of patients with, COVID-19 using pathways such as Emergency Use...
Therapies have been developed in the last couple of years to allow vaccination against, or treatment of patients with, COVID-19 using pathways such as Emergency Use Authorization (EUA) in the USA and Conditional Marketing Authorization (CMA) in the EU and UK. However, nonclinical studies were performed to allow such authorization and these were reviewed for 6 vaccines, 7 biological (monoclonal antibodies [mAbs]) and 4 small molecule therapies to examine whether the number and types of studies normally needed for regulatory agency authorization have been reduced. Results showed that the short answer is generally no. Thus, a battery of immunogenicity/efficacy or related pharmacology/biological activity studies showing utility against SARS-CoV-2 were performed as well as general toxicity studies across all 3 compound classes along with pharmacokinetic studies for mAbs and small molecules and, reproduction toxicity testing for vaccines and small molecules; additionally, genotoxicity testing occurred for small molecules. What was different from conventional, lengthy drug development, was that for vaccines and small molecules, leverage to existing platform technology or data available for other development programs, respectively, occurred. Recognition that mAbs can target the spike protein leading to neutralization allowed rapid development into clinical candidates.
Topics: Antibodies, Monoclonal; Antibodies, Viral; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35609793
DOI: 10.1016/j.yrtph.2022.105189