scholarly journals Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro

2021 ◽  
Vol 183 ◽  
pp. 182-192
Author(s):  
Ruyu Wang ◽  
Qing Hu ◽  
Haonan Wang ◽  
Guanghao Zhu ◽  
Mengge Wang ◽  
...  
Keyword(s):  
Vitamin K3 ◽  
Covalent Inhibitors

Novel chemistry for covalent inhibitors

2020 ◽  
Vol 19 (11) ◽  
pp. 754-754
Author(s):  
Megan Cully
Keyword(s):  
Covalent Inhibitors

Metabolic Studies of Vitamin K1-14C and Menadione-14C in the Normal and Hepatectomized Rats

1968 ◽  
Vol 19 (03/04) ◽  
pp. 383-388 ◽  
Author(s):  
R Losito ◽  
C. A Owen ◽  
E. V Flock ◽  
Keyword(s):  
Enzymatic Hydrolysis ◽  
Oral Anticoagulants ◽  
Urinary Metabolites ◽  
The Other ◽  
Vitamin K1 ◽  
Vitamin K3 ◽  
Metabolic Studies ◽  
Intact Rats

SummaryThe metabolism of vitamin K1- 14C and menadione-14C (vitamin K3-14C) was studied in normal and hepateetomized rats. After the administration of menadione, about 70% of the 14C was excreted in the urine in 24 hrs in both types of rats. Two urinary metabolites were identified by enzymatic hydrolysis: one a glucuronide and the other a sulfate of reduced menadione. Thus, the liver is not necessary for the metabolism of menadione. In the vitamin K1 studies, the intact rats excreted only 10% of the 14C and the hepatectomized rats excreted less than 0.5%. The retention of vitamin K1 may explain its superiority over menadione as an antidote for overdosages of oral anticoagulants.

Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome

2019 ◽  
Author(s):  
Patrick R. A. Zanon ◽  
Lisa Lewald ◽  
Stephan M. Hacker
Keyword(s):  
Binding Sites ◽  
Bacterial Resistance ◽  
Mevalonate Pathway ◽  
Rapid Development ◽  
High Reactivity ◽  
Functional Importance ◽  
Essential Proteins ◽  
Covalent Inhibitors ◽  
Druggable Targets ◽  
Covalent Ligands

Rapid development of bacterial resistance has led to an urgent need to find new druggable targets for antibiotics. In this context, residue-specific chemoproteomic approaches enable proteome-wide identification of binding sites for covalent inhibitors. Here, we describe isotopically labeled desthiobiotin azide (isoDTB) tags that are easily synthesized, shorten the chemoproteomic workflow and allow an increased coverage of cysteines in bacterial systems. We quantify 59% of all cysteines in essential proteins in <i>Staphylococcus aureus</i> and discover 88 cysteines with high reactivity, which correlates with functional importance. Furthermore, we identify 268 cysteines that are engaged by covalent ligands. We verify inhibition of HMG-CoA synthase, which will allow addressing the bacterial mevalonate pathway through a new target. Overall, a comprehensive map of the bacterial cysteinome is obtained, which will facilitate the development of antibiotics with novel modes-of-action.

Covalent-Fragment Screening of Brd4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites

2019 ◽  
Author(s):  
Michael Olp ◽  
Daniel Sprague ◽  
Stefan Kathman ◽  
Ziyang Xu ◽  
Alexandar Statsyuk ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Binding Site ◽  
Binding Sites ◽  
Computational Prediction ◽  
Chemical Probes ◽  
Computational Docking ◽  
Fragment Screening ◽  
Covalent Inhibitors ◽  
Bet Protein ◽  
Proof Of Principle

<p>Brd4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin. Alternative chemical probes that act orthogonally to the highly-conserved acetyl-lysine binding sites may exhibit selectivity within the BET family and avoid recently reported toxicity in clinical trials of BET bromodomain inhibitors. Here, we report the first identification of a ligandable site on a bromodomain outside the acetyl-lysine binding site. Inspired by our computational prediction of hotspots adjacent to non-homologous cysteine residues within the <i>C</i>-terminal Brd4 bromodomain (Brd4-BD2), we performed a mid-throughput mass spectrometry screen to identify cysteine-reactive fragments that covalently and selectively modify Brd4. Subsequent mass spectrometry, NMR and computational docking analyses of electrophilic fragment hits revealed a novel ligandable site near Cys356 that is unique to Brd4 among all human bromodomains. This site is orthogonal to the Brd4-BD2 acetyl-lysine binding site as Cys356 modification did not impact binding of the pan-BET bromodomain inhibitor JQ1 in fluorescence polarization assays. Finally, we tethered covalent fragments to JQ1 and performed NanoBRET assays to provide proof of principle that this orthogonal site can be covalently targeted in intact human cells. Overall, we demonstrate the potential of targeting sites orthogonal to bromodomain acetyl-lysine binding sites to develop bivalent and covalent inhibitors that displace Brd4 from chromatin.</p>

Anticancer Vitamin K3 Analogs: A Review

2016 ◽  
Vol 16 (8) ◽  
pp. 1017-1030 ◽  
Author(s):  
Kirti D. Badave ◽  
Ayesha A. Khan ◽  
Sandhya Y. Rane
Keyword(s):  
Vitamin K3

scholarly journals Effects of Sources and Forms of Vitamin K3 on Its Storage Stability in Vitamin Premixes or Vitamin Trace Mineral Premixes

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1140
Author(s):  
Huakai Wang ◽  
Pan Yang ◽  
Longxian Li ◽  
Nan Zhang ◽  
Yongxi Ma ◽  
...  
Keyword(s):  
Relative Humidity ◽  
Storage Time ◽  
Storage Stability ◽  
Choline Chloride ◽  
Crystal Form ◽  
Negative Effects ◽  
Trace Mineral ◽  
Vitamin K3 ◽  
Choline Group ◽  
Micro Sphere

Six types of vitamin K3 (VK3); two sources (menadione sodium bisulfite, MSB; menadione nicotinamide bisulfite, MNB), and three different forms (crystal, micro-capsule, and micro-sphere) were used to determine the retention of VK3 in vitamin premixes (Experiment 1) or vitamin trace mineral (VTM) premixes (Experiment 2) after 1, 2, 3, and 6 months of storage. The retention of VK3 in vitamin premixes was evaluated at 25 °C/60% relative humidity or 40 °C/75% relative humidity in an incubator in Experiment 1 and in VTM premixes (choline chloride: 0 vs. 16,000 mg/kg) stored at room temperature in Experiment 2. The VK3 retention in vitamin premix or VTM premix decreased significantly with the extension of storage time (p < 0.05). In Experiment 1, the VK3 retention was higher in the 25 °C/60% incubator (56%) than in the 40 °C/75% incubator (28%). The MNB retention (52%) was higher than MSB retention (32%). The retention of VK3 in micro-capsules (43%) or micro-spheres (48%) was higher than the crystal form (35%) after six months of storage. In Experiment 2, there was no difference between the retention of MSB (49%) or MNB (47%). The retention of VK3 of micro-capsule (51%) or micro-sphere (54%) was higher than that of crystal form (40%). The VK3 retention was higher in the choline-free group (51%) than in the choline group (47%) after six months of storage. Finally, the predicted equations of VK3 retention with storage time in vitamin premixes or VTM premixes were established. The R2 of the prediction equations was ≥0.9005, indicating that time is an important factor in predicting VK3 retention. In conclusion, the higher temperature-relative humidity, choline had negative effects on VK3 retention during premix storage. MNB retention was higher than MSB during storage of vitamin premix. The encapsulated forms of VK3, micro-capsules and micro-spheres, could improve VK3 storage stability in vitamin premix and VTM premix.

scholarly journals FGFR-TKI resistance in cancer: current status and perspectives

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sitong Yue ◽  
Yukun Li ◽  
Xiaojuan Chen ◽  
Juan Wang ◽  
Meixiang Li ◽  
...  
Keyword(s):  
Gene Fusion ◽  
Kinase Inhibitors ◽  
Current Status ◽  
Great Success ◽  
Fibroblast Growth Factor Receptors ◽  
Pathway Activation ◽  
Tki Resistance ◽  
Covalent Inhibitors ◽  
And Migration ◽  
Dual Target

AbstractFibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.

Descriptors for vitamin K3 (menadione); calculation of biological and physicochemical properties

2021 ◽  
Vol 330 ◽  
pp. 115707
Author(s):  
Xiangli Liu ◽  
Michael H. Abraham ◽  
William E. Acree
Keyword(s):  
Physicochemical Properties ◽  
Vitamin K3
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