Target Protein
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2022 ◽  
Evianne Rovers ◽  
Matthieu Schapira

Proximity pharmacology (ProxPharm) is a novel paradigm in drug discovery where a small molecule brings two proteins in close proximity to elicit a signal, generally from one protein onto another. The potential of ProxPharm compounds as a new therapeutic modality is firmly established by proteolysis targeting chimeras (PROTACs) that bring an E3 ubiquitin ligase in proximity to a target protein to induce ubiquitination and subsequent degradation of the target protein. The concept can be expanded to induce other post-translational modifications via the recruitment of different types of protein-modifying enzymes. To survey the human proteome for opportunities in proximity pharmacology, we systematically mapped non-catalytic drug binding pockets on the structure of protein-modifying enzymes available from the Protein Databank. In addition to binding sites exploited by previously reported ProxPharm compounds, we identified putative ligandable non-catalytic pockets in 188 kinases, 42 phosphatases, 26 deubiquitinases, 9 methyltransferases, 7 acetyltransferases, 7 glycosyltransferases, 4 deacetylases, 3 demethylases and 2 glycosidases, including cavities occupied by chemical matter that may serve as starting points for future ProxPharm compounds. This systematic survey confirms that proximity pharmacology is a versatile modality with largely unexplored and promising potential, and reveals novel opportunities to pharmacologically rewire molecular circuitries.

2022 ◽  
Geetika Aggarwal ◽  
Subhashis Banerjee ◽  
Spencer A. Jones ◽  
Monica D. Pavlack ◽  
Yousri Benchaar ◽  

Loss-of-function GRN mutations result in progranulin haploinsufficiency and are a common cause of frontotemporal dementia (FTD). Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but ASO-based strategies for increasing target protein levels are still relatively limited. Here, we report the use of ASOs to increase progranulin protein levels by targeting the miR-29b binding site in the 3′ UTR of the GRN mRNA, resulting in increased translation.

2022 ◽  
Vol 24 (1) ◽  
pp. 141-151
VithyaEswari. D ◽  
R. Subashkumar ◽  

Phytolacca octandra is a perennial usually about 1m high herb, dense and erect in full sun. As only few reports were available on the studies about the bioactive compounds and various activities in the Phytolacca octandra, the present study focuses on the bio active compounds attributed to antibacterial activity in the plant extracts by Gas Chromatography – Mass Spectrometry (GCMS) and molecular docking methods. Antibacterial activity of Phytolacca octandra showed maximum inhibitory zones of 21mm, 18mm, 19mm, 19mm and 20mm against respective organisms for 25mg/ml of acetone extracts. The outcome of Phytolacca octandra extracts that was exposed to GC-MS analysis, showed the presence of 20 more compounds. The most identified compounds to have anti-oxidant activity are Dodecane, Octadecane and Octacosane. The other major compounds present in extract are Cyclohexen-oxopropyl, 1,2-Benzenedicarboxylic acid.The overall docking energies of the target protein, rhamnolipids biosynthesis 3-oxoacyl-[acyl-carrier-protein] reductase with quercetin with the number of hydrogen bonds were presented in the study; The docking report revealed –8.01Kcal/Mol binding energies and 8 hydrogen bonding between the Phytolacca octandra compound, quercetin and the target binding protein, rhlG of infection causing pathogen Staphylococcus aureus.

2022 ◽  
pp. 002215542110649
Joshua T. Dodge ◽  
Andrew D. Doyle ◽  
Ana C. Costa-da-Silva ◽  
Christopher T. Hogden ◽  
Eva Mezey ◽  

Multiplex immunofluorescence (mIF) is an effective technique for the maximal visualization of multiple target proteins in situ. This powerful tool is mainly limited by the spectral overlap of the currently available synthetic fluorescent dyes. The fluorescence excitation wavelengths ranging between 405 and 488 nm are rarely used in mIF imaging and serve as a logical additional slot for a fluorescent probe. In the present study, we demonstrate that the addition of 2,3,4,5,6-pentafluoroaniline to Atto 465 NHS ester, creating Atto 465-pentafluoroaniline (Atto 465-p), generates a bright nuclear stain in the violet-blue region of the visible spectrum. This allows the 405 nm excitation and emission, classically used for nuclear counterstains, to be used for the detection of another target protein. This increases the flexibility of the mIF panel and, with appropriate staining and microscopy, enables the quantitative analysis of at least six targets in one tissue section. (J Histochem Cytochem XX: XXX–XXX, XXXX)

2022 ◽  
Vol 12 ◽  
Lifang Ye ◽  
Yu Zuo ◽  
Fang Chen ◽  
Qinglin Peng ◽  
Xin Lu ◽  

Immune-mediated necrotizing myopathy (IMNM) is characterized by manifestation of myonecrosis and regeneration of muscle fibers; however, the underlying pathogenesis remains unclear. This study aimed to investigate the role and mechanism of miR-18a-3p and its target RNA-binding protein HuR in IMNM. HuR and miR-18a-3p levels were detected in the skeletal muscles of 18 patients with IMNM using quantitative reverse-transcription real-time polymerase chain reaction (qRT-PCR) and western blotting analysis. Human myoblasts were transfected with small interfering RNA targeting HuR and miR-18a-3p mimic or inhibitor. Myogenic differentiation markers, myogenin and myosin heavy chain, were analyzed by qRT-PCR, western blotting analysis, and immunofluorescence staining. The results showed that miR-18a-3p was upregulated (p=0.0002), whereas HuR was downregulated (p=0.002) in the skeletal muscles of patients with IMNM. The expression of miR-18a-3p in patients with IMNM was negatively correlated with those of HuR (r = -0.512, p = 0.029). We also found that disease activity was positively correlated with HuR expression (r = 0.576, p = 0.012) but muscle activity was negatively correlated with miR-18a-3p expression (r = -0.550, p = 0.017). Besides, bioinformatics analysis and dual-luciferase reporter assays suggested that miR-18a-3p could directly target HuR. Cellular experiments showed that overexpression of miR-18a-3p inhibited myogenic differentiation by targeting HuR, whereas inhibition of miR-18a-3p led to opposite results. Therefore, miR-18a-3p and its target protein HuR may be responsible for modulating the myogenic process in IMNM and can thus be therapeutic targets for the same.

2022 ◽  
Daniel I Benjamin ◽  
Pieter I Both ◽  
Joel S Benjamin ◽  
Christopher W Nutter ◽  
Jenna H Tan ◽  

Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet, or exogenously administered, promotes a deep quiescent state in muscle stem cells(MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Further, we show that ketone bodies, specifically b hydroxybutyrate, directly promote MuSC deep quiescence via a non-metabolic mechanism. We show that b-hydroxybutyrate functions as an HDAC inhibitor within MuSCs leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.

2022 ◽  
Luke Martin Simpson ◽  
Lorraine Glennie ◽  
Jennifer Crooks ◽  
Natalia Shpiro ◽  
Gopal Sapkota

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261971
Jialu Qiao ◽  
Qian Peng ◽  
Feng Qian ◽  
Qiang You ◽  
Lingyan Feng ◽  

MicroRNAs (miRNAs) are important molecules that mediate virus-host interactions, mainly by regulating gene expression via gene silencing. Here, we demonstrated that HIV-1 infection upregulated miR-210-5p in HIV-1-inoculated cell lines and in the serum of HIV-1-infected individuals. Luciferase reporter assays and western blotting confirmed that a target protein of miR-210-5p, TGIF2, is regulated by HIV-1 infection. Furthermore, HIV-1 Vpr protein induced miR-210-5p expression. The use of a miR-210-5p inhibitor and TGIF2 overexpression showed that Vpr upregulated miR-210-5p and thereby downregulated TGIF2, which might be one of the mechanisms used by Vpr to induce G2 arrest. Moreover, we identified a transcription factor, NF-κB p50, which upregulated miR-210-5p in response to Vpr protein. In conclusion, we identified a mechanism whereby miR-210-5p, which is induced upon HIV-1 infection, targets TGIF2. This pathway was initiated by Vpr protein activating NF-κB p50, which promoted G2 arrest. These alterations orchestrated by miRNA provide new evidence on how HIV-1 interacts with its host during infection and increase our understanding of the mechanism by which Vpr regulates the cell cycle.

Umair Ilyas ◽  
Shagufta Naaz ◽  
Syed Aun Muhammad ◽  
Humaira Nadeem ◽  
Reem Altaf ◽  

Background: The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate for this therapeutic failure. Objectives: The current study demonstrated whether N-protected and deprotected amino acid derivatives of 2-aminopyridine could attenuate tumor development using colorectal cancer cell lines. Methods: Biological assays were performed to investigate the anticancer potential of synthesized compounds. The in silico ADME profiling and docking studies were also performed by docking the designed compounds against the active binding site of beta-catenin (CTNNB1) to analyze the binding mode of these compounds. Four derivatives 4a, 4b, 4c, and 4d were selected for investigation of in vitro anticancer potential using colorectal cancer cell line HCT 116. The anti-tumor activities of synthesized compounds were further validated by evaluating the inhibitory effects of these compounds on the target protein beta-catenin through in vitro enzyme inhibitory assay. Results: The docking analysis revealed favorable binding energies and interactions with the target proteins. The in vitro MTT assay on colorectal cancer cell line HCT 116 and HT29 revealed potential anti-tumor activities with an IC50 range of 3.7-8.1µM and 3.27-7.7 µM, respectively. The inhibitory properties of these compounds on the concentration of beta-catenin by ELISA revealed significant percent inhibition of target protein at 100 µg/ml. Conclusion: In conclusion, the synthesized compounds showed significant anti-tumor activities both in silico and in vitro, having potential for further investigating its role in colorectal cancer.

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