Nucleic Acid-Targeted Small Molecules have Therapeutic Potential in the Treatment of Spinal Muscular Atrophy: Small-molecule drugs that can selectively bind RNA and modulate pre-mRNA splicing have potential as a treatment strategy for human disease, inclu

2018 ◽  
Vol 176 (8) ◽  
pp. 1698-1699
Keyword(s):  
Nucleic Acid ◽  
Spinal Muscular Atrophy ◽  
Small Molecules ◽  
Small Molecule ◽  
Treatment Strategy ◽  
Human Disease ◽  
Therapeutic Potential ◽  
Muscular Atrophy ◽  
Mrna Splicing ◽  
Small Molecule Drugs

scholarly journals Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shiori Ando ◽  
Shunya Suzuki ◽  
Shoichi Okubo ◽  
Kazuki Ohuchi ◽  
Kei Takahashi ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Small Molecule ◽  
Therapeutic Potential ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Tolerability Profile ◽  
Loss Of Function ◽  
Cryptic Exon

Abstract Spinal muscular atrophy (SMA) is a motor neuron disease, typically resulting from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Nusinersen/SPINRAZA, a splice-switching oligonucleotide that modulates SMN2 (a paralog of SMN1) splicing and consequently increases SMN protein levels, has a therapeutic effect for SMA. Previously reported small-molecule SMN2 splicing modulators such as risdiplam/EVRYSDI and its analog SMN-C3 modulate not only the splicing of SMN2 but also that of secondary splice targets, including forkhead box protein M1 (FOXM1). Through screening SMA patient-derived fibroblasts, a novel small molecule, designated TEC-1, was identified that selectively modulates SMN2 splicing over three secondary splice targets. TEC-1 did not strongly affect the splicing of FOXM1, and unlike risdiplam, did not induce micronucleus formation. In addition, TEC-1 showed higher selectively on galactosylceramidase and huntingtin gene expression compared to previously reported compounds (e.g., SMN-C3) due to off-target effects on cryptic exon inclusion and nonsense-mediated mRNA decay. Moreover, TEC-1 significantly ameliorated the disease phenotype in an SMA murine model in vivo. Thus, TEC-1 may have promising therapeutic potential for SMA, and our study demonstrates the feasibility of RNA-targeting small-molecule drug development with an improved tolerability profile.

scholarly journals Detection of Spinal Muscular Atrophy Using a Duplexed Real-Time PCR Approach With Locked Nucleic Acid-Modified Primers

2021 ◽  
Vol 41 (1) ◽  
pp. 101-107
Author(s):  
Jianyan Pan ◽  
Chunhua Zhang ◽  
Yanling Teng ◽  
Sijing Zeng ◽  
Siyi Chen ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Spinal Muscular Atrophy ◽  
Real Time ◽  
Real Time Pcr ◽  
Muscular Atrophy ◽  
Locked Nucleic Acid

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

2020 ◽  
Author(s):  
Chao Wang ◽  
Juan Diez ◽  
Hajeung Park ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Hydroxamic Acid ◽  
Therapeutic Potential ◽  
Preceding Paper ◽  
Close Relative ◽  
Specific Inhibition ◽  
Selective Inhibitors

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

scholarly journals How ‘Protein-Docking’ Translates into the New Emerging Field of Docking Small Molecules to Nucleic Acids?

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2749
Author(s):  
Francesca Tessaro ◽  
Leonardo Scapozza
Keyword(s):  
Molecular Docking ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Small Molecules ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Mrna Level ◽  
Protein Docking ◽  
Structural Nature ◽  
Rigid Docking

In this review, we retraced the ‘40-year evolution’ of molecular docking algorithms. Over the course of the years, their development allowed to progress from the so-called ‘rigid-docking’ searching methods to the more sophisticated ‘semi-flexible’ and ‘flexible docking’ algorithms. Together with the advancement of computing architecture and power, molecular docking’s applications also exponentially increased, from a single-ligand binding calculation to large screening and polypharmacology profiles. Recently targeting nucleic acids with small molecules has emerged as a valuable therapeutic strategy especially for cancer treatment, along with bacterial and viral infections. For example, therapeutic intervention at the mRNA level allows to overcome the problematic of undruggable proteins without modifying the genome. Despite the promising therapeutic potential of nucleic acids, molecular docking programs have been optimized mostly for proteins. Here, we have analyzed literature data on nucleic acid to benchmark some of the widely used docking programs. Finally, the comparison between proteins and nucleic acid targets docking highlighted similarity and differences, which are intrinsically related to their chemical and structural nature.

Fragment-based drug design of nature-inspired compounds

2019 ◽  
Vol 4 (9) ◽  
Author(s):  
Abdulkarim Najjar ◽  
Abdurrahman Olğaç ◽  
Fidele Ntie-Kang ◽  
Wolfgang Sippl
Keyword(s):  
Drug Design ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Pocket ◽  
Biological Macromolecules ◽  
Drug Candidates ◽  
Fragment Screening ◽  
Small Molecule Drugs ◽  
Lead Generation ◽  
Hit Identification

Abstract Natural product (NP)-derived drugs can be extracts, biological macromolecules, or purified small molecule substances. Small molecule drugs can be originally purified from NPs, can represent semisynthetic molecules, natural fragments containing small molecules, or are fully synthetic molecules that mimic natural compounds. New semisynthetic NP-like drugs are entering the pharmaceutical market almost every year and reveal growing interests in the application of fragment-based approaches for NPs. Thus, several NP databases were constructed to be implemented in the fragment-based drug design (FBDD) workflows. FBDD has been established previously as an approach for hit identification and lead generation. Several biophysical and computational methods are used for fragment screening to identify potential hits. Once the fragments within the binding pocket of the protein are identified, they can be grown, linked, or merged to design more active compounds. This work discusses applications of NPs and NP scaffolds to FBDD. Moreover, it briefly reviews NP databases containing fragments and reports on case studies where the approach has been successfully applied for the design of antimalarial and anticancer drug candidates.

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

scholarly journals Targeting Th17 Cells with Small Molecules and Small Interference RNA

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Hui Lin ◽  
Pingfang Song ◽  
Yi Zhao ◽  
Li-Jia Xue ◽  
Yi Liu ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Th17 Cells ◽  
Therapeutic Potential ◽  
Random Sequence ◽  
Orphan Receptor ◽  
T Helper 17 ◽  
Small Interference Rna ◽  
Chemical Screen ◽  
Interference Rna

T helper 17 (Th17) cells play a central role in inflammatory and autoimmune diseases via the production of proinflammatory cytokines interleukin- (IL-) 17, IL-17F, and IL-22. Anti-IL-17 monoclonal antibodies show potent efficacy in psoriasis but poor effect in rheumatoid arthritis (RA) and Crohn’s disease. Alternative agents targeting Th17 cells may be a better way to inhibit the development and function of Th17 cells than antibodies of blocking a single effector cytokine. Retinoic acid-related orphan receptor gamma t (RORγt) which acts as the master transcription factor of Th17 differentiation has been an attractive pharmacologic target for the treatment of Th17-mediated autoimmune disease. Recent progress in technology of chemical screen and engineering nucleic acid enable two new classes of therapeutics targeting RORγt. Chemical screen technology identified several small molecule specific inhibitors of RORγt from a small molecule library. Systematic evolution of ligands by exponential enrichment (SELEX) technology enabled target specific aptamers to be isolated from a random sequence oligonucleotide library. In this review, we highlight the development and therapeutic potential of small molecules inhibiting Th17 cells by targeting RORγt and aptamer mediated CD4+T cell specific delivery of small interference RNA against RORγt gene expression to inhibit pathogenic effector functions of Th17 lineage.

scholarly journals Pharmacogenomics: An Update on Biologics and Small-Molecule Drugs in the Treatment of Psoriasis

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1398
Author(s):  
Valerio Caputo ◽  
Claudia Strafella ◽  
Terenzio Cosio ◽  
Caterina Lanna ◽  
Elena Campione ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Clinical Utility ◽  
Tumor Necrosis ◽  
Drug Efficacy ◽  
Dimethyl Fumarate ◽  
Biological Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor ◽  
Pharmacogenomic Studies

Pharmacogenomic studies allowed the reasons behind the different responses to treatments to be understood. Its clinical utility, in fact, is demonstrated by the reduction in adverse drug reaction incidence and the improvement of drug efficacy. Pharmacogenomics is an important tool that is able to improve the drug therapy of different disorders. In particular, this review will highlight the current pharmacogenomics knowledge about biologics and small-molecule treatments for psoriasis. To date, studies performed on genes involved in the metabolism of biological drugs (tumor necrosis factor inhibitors and cytokines inhibitors) and small molecules (apremilast, dimethyl fumarate, and tofacitinib) have provided conflicting results, and further investigations are necessary in order to establish a set of biomarkers to be introduced into clinical practice.

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