scholarly journals Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening

ACS Omega ◽  
2020 ◽  
Vol 5 (47) ◽  
pp. 30625-30632
Author(s):  
Liqun Xia ◽  
Danyang Shen ◽  
Huan Wang ◽  
Liangliang Ren ◽  
Yi Chen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Repurposing ◽  
Testicular Receptor ◽  
Testicular Receptor 4

Construction of lux-based promoter-reporter platforms in Mycobacterium bovis BCG for screening of drug repurposing small-molecule compounds as new anti-tuberculosis drugs

2021 ◽  
Author(s):  
Li Zhu ◽  
Annie Wing-tung Lee ◽  
Kelvin Ka-Lok WU ◽  
Peng GAO ◽  
Kingsley King-Gee Tam ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Repurposing ◽  
Virulence Gene ◽  
Multidrug Resistant ◽  
Rapid Screening ◽  
Human Macrophage ◽  
Tuberculosis Complex ◽  
Low Cytotoxicity ◽  
Screening Platform

The emergence of multidrug-resistant strains and hyper-virulent strains of Mycobacterium tuberculosis are big therapeutic challenges for tuberculosis (TB) control. Repurposing bioactive small-molecule compounds has recently become a new therapeutic approach against TB. This study aimed to construct a rapid screening system to identify novel anti-TB agents from a library of small-molecule compounds. In this study, a total of 320 small-molecule compounds were used to screen for their ability to suppress the expression of a key virulence gene, phoP, of M. tuberculosis complex using luminescence (lux)-based promoter-reporter platforms. The minimum inhibitory and bactericidal concentrations on drug-resistant M. tuberculosis and cytotoxicity to human macrophage were determined. RNA-sequencing (RNA-seq) was conducted to determine the drug mechanisms of the selected compounds as novel antibiotics or anti-virulent agents against the M. tuberculosis complex. Six compounds displayed bactericidal activity against M. bovis BCG, in which Ebselen demonstrated the lowest cytotoxicity to macrophage and was considered as a potential antibiotic for TB. Another ten compounds did not inhibit the in vitro growth of the M. tuberculosis complex but down-regulated the expression of phoP specifically. Of them, ST-193 and ST-193 (hydrochloride) showed low cytotoxicity and could dysregulate the entire phoP-associated gene network, and thus identified as potential anti-virulence agents for M. tuberculosis. This study provides a rapid screening platform coupled with a systematic validation and eventually suggested one potential antibiotic and two anti-virulence agents for M. tuberculosis infections.

scholarly journals Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells

2018 ◽  
Vol 11 (549) ◽  
pp. eaat7951 ◽  
Author(s):  
Daniel M. Foulkes ◽  
Dominic P. Byrne ◽  
Wayland Yeung ◽  
Safal Shrestha ◽  
Fiona P. Bailey ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Drug Repurposing ◽  
Protein Kinase Inhibitors ◽  
Cellular Mechanisms ◽  
Cellular Analysis

A major challenge associated with biochemical and cellular analysis of pseudokinases is a lack of target-validated small-molecule compounds with which to probe function. Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, including the canonical AKT signaling module. There is substantial evidence that human TRIB2 promotes survival and drug resistance in solid tumors and blood cancers and therefore is of interest as a therapeutic target. The unusual TRIB2 pseudokinase domain contains a unique cysteine-rich C-helix and interacts with a conserved peptide motif in its own carboxyl-terminal tail, which also supports its interaction with E3 ubiquitin ligases. We found that TRIB2 is a target of previously described small-molecule protein kinase inhibitors, which were originally designed to inhibit the canonical kinase domains of epidermal growth factor receptor tyrosine kinase family members. Using a thermal shift assay, we discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS) and used a drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro. TRIB2 destabilizing agents, including the covalent drug afatinib, led to rapid TRIB2 degradation in human AML cancer cells, eliciting tractable effects on signaling and survival. Our data reveal new drug leads for the development of TRIB2-degrading compounds, which will also be invaluable for unraveling the cellular mechanisms of TRIB2-based signaling. Our study highlights that small molecule–induced protein down-regulation through drug “off-targets” might be relevant for other inhibitors that serendipitously target pseudokinases.

scholarly journals Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen

2016 ◽  
Vol 22 (10) ◽  
pp. 1101-1107 ◽  
Author(s):  
Miao Xu ◽  
Emily M Lee ◽  
Zhexing Wen ◽  
Yichen Cheng ◽  
Wei-Kai Huang ◽  
...  
Keyword(s):  
Cell Death ◽  
Virus Infection ◽  
Small Molecule ◽  
Zika Virus ◽  
Small Molecule Inhibitors ◽  
Drug Repurposing ◽  
Neural Cell ◽  
Zika Virus Infection

scholarly journals Lung on a Chip Development from Off-Stoichiometry Thiol–Ene Polymer

Micromachines ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 546
Author(s):  
Roberts Rimsa ◽  
Artis Galvanovskis ◽  
Janis Plume ◽  
Felikss Rumnieks ◽  
Karlis Grindulis ◽  
...  
Keyword(s):  
Small Molecule ◽  
Light Transmission ◽  
Umbilical Vein ◽  
Drug Repurposing ◽  
In Vitro Models ◽  
Enzymatic Reactions ◽  
Promising Alternative ◽  
Prototype Development ◽  
Alternative Material

Current in vitro models have significant limitations for new respiratory disease research and rapid drug repurposing. Lung on a chip (LOAC) technology offers a potential solution to these problems. However, these devices typically are fabricated from polydimethylsiloxane (PDMS), which has small hydrophobic molecule absorption, which hinders the application of this technology in drug repurposing for respiratory diseases. Off-stoichiometry thiol–ene (OSTE) is a promising alternative material class to PDMS. Therefore, this study aimed to test OSTE as an alternative material for LOAC prototype development and compare it to PDMS. We tested OSTE material for light transmission, small molecule absorption, inhibition of enzymatic reactions, membrane particle, and fluorescent dye absorption. Next, we microfabricated LOAC devices from PDMS and OSTE, functionalized with human umbilical vein endothelial cell (HUVEC) and A549 cell lines, and analyzed them with immunofluorescence. We demonstrated that compared to PDMS, OSTE has similar absorption of membrane particles and effect on enzymatic reactions, significantly lower small molecule absorption, and lower light transmission. Consequently, the immunofluorescence of OSTE LOAC was significantly impaired by OSTE optical properties. In conclusion, OSTE is a promising material for LOAC, but optical issues should be addressed in future LOAC prototypes to benefit from the material properties.

scholarly journals Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine and Pyronaridine: In vitro Activity Against SARS-CoV-2 and Potential Mechanisms

2020 ◽  
Author(s):  
Ana C. Puhl ◽  
Ethan James Fritch ◽  
Thomas R. Lane ◽  
Longping V. Tse ◽  
Boyd L. Yount ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Ebola Virus ◽  
Early Stage ◽  
Drug Repurposing ◽  
Marburg Virus ◽  
Small Molecule Drugs ◽  
Speed Up

AbstractSARS-CoV-2 is a newly identified virus that has resulted in over 1.3 M deaths globally and over 59 M cases globally to date. Small molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola virus and demonstrated activity against SARS-CoV-2 in vivo. Most notably the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small molecule drugs that are active against Ebola virus would seem a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg virus in vitro in HeLa cells and of mouse adapted Ebola virus in mouse in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7 and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We have also tested them in a pseudovirus assay and used microscale thermophoresis to test the binding of these molecules to the spike protein. They bind to spike RBD protein with Kd values of 339 nM and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 hence justifying in vivo evaluation. We also provide novel insights into their mechanism which is likely lysosomotropic.

scholarly journals Extensive Reliability Evaluation of Docking-Based Target-Fishing Strategies

2019 ◽  
Vol 20 (5) ◽  
pp. 1023 ◽  
Author(s):  
Margherita Lapillo ◽  
Tiziano Tuccinardi ◽  
Adriano Martinelli ◽  
Marco Macchia ◽  
Antonio Giordano ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Structures ◽  
Drug Repurposing ◽  
Protein Targets ◽  
Drug Candidates ◽  
Fishing Strategies ◽  
Benchmark Database ◽  
Speed Up ◽  
Actual Target ◽  
Target Fishing

The development of target-fishing approaches, aimed at identifying the possible protein targets of a small molecule, represents a hot topic in medicinal chemistry. A successful target-fishing approach would allow for the elucidation of the mechanism of action of all therapeutically interesting compounds for which the actual target is still unknown. Moreover, target-fishing would be essential for preventing adverse effects of drug candidates, by predicting their potential off-targets, and it would speed up drug repurposing campaigns. However, due to the huge number of possible protein targets that a small-molecule might interact with, experimental target-fishing approaches are out of reach. In silico target-fishing represents a valuable alternative, and examples of receptor-based approaches, exploiting the large number of crystallographic protein structures determined to date, have been reported in the literature. To the best of our knowledge, no proper evaluation of such approaches is, however, reported yet. In the present work, we extensively assessed the reliability of docking-based target-fishing strategies. For this purpose, a set of X-ray structures belonging to different targets was selected, and a dataset of compounds, including 10 experimentally active ligands for each target, was created. A target-fishing benchmark database was then obtained, and used to assess the performance of 13 different docking procedures, in identifying the correct target of the dataset ligands. Moreover, a consensus docking-based target-fishing strategy was developed and evaluated. The analysis highlighted that specific features of the target proteins could affect the reliability of the protocol, which however, proved to represent a valuable tool in the proper applicability domain. Our study represents the first extensive performance assessment of docking-based target-fishing approaches, paving the way for the development of novel efficient receptor-based target fishing strategies.

scholarly journals Targeting ACE2-RBD interaction as a platform for COVID19 therapeutics: Development and drug repurposing screen of an AlphaLISA proximity assay

2020 ◽  
Author(s):  
Quinlin M. Hanson ◽  
Kelli M. Wilson ◽  
Min Shen ◽  
Zina Itkin ◽  
Richard T. Eastman ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Potential Therapeutic Target ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interaction ◽  
Small Molecule Drugs ◽  
Protein Receptor ◽  
Direct Binding

AbstractThe COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering rapid response from scientists across the globe. Host cell invasion is initiated through direct binding of the viral spike protein to the host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting the spike-ACE2 interaction is a potential therapeutic target for treating COVID-19. We have developed a proximity-based AlphaLISA assay to measure binding of SARS-CoV-2 spike protein Receptor Binding Domain (RBD) to ACE2. Utilizing this assay platform, a drug-repurposing screen against 3,384 small molecule drugs and pre-clinical compounds was performed, yielding 25 high-quality, small-molecule hits that can be evaluated in cell-based models. This established AlphaLISA RBD-ACE2 platform can facilitate evaluation of biologics or small molecules that can perturb this essential viral-host interaction to further the development of interventions to address the global health pandemic.

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