scholarly journals Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 788
Author(s):  
Juan Carlos Lacal ◽  
Tahl Zimmerman ◽  
Joaquín M. Campos
Keyword(s):  
Precision Medicine ◽  
Pathogenic Bacteria ◽  
Antitumor Agents ◽  
Structural Parameters ◽  
Choline Kinase ◽  
Membrane Phospholipids ◽  
Inflammatory Processes ◽  
Quantitative Structure Activity Relationships ◽  
Novel Drug ◽  
Anticancer Compound

Choline kinase (ChoK) is a cytosolic enzyme that catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is required for the synthesis of key membrane phospholipids and is involved in malignant transformation in a large variety of human tumours. Active compounds against ChoK have been identified and proposed as antitumor agents. The ChoK inhibitory and antiproliferative activities of symmetrical bispyridinium and bisquinolinium compounds have been defined using quantitative structure–activity relationships (QSARs) and structural parameters. The design strategy followed in the development of the most active molecules is presented. The selective anticancer activity of these structures is also described. One promising anticancer compound has even entered clinical trials. Recently, ChoKα inhibitors have also been proposed as a novel therapeutic approach against parasites, rheumatoid arthritis, inflammatory processes, and pathogenic bacteria. The evidence for ChoKα as a novel drug target for approaches in precision medicine is discussed.

scholarly journals Intermedilysin cytolytic activity depends on heparan sulfates and membrane composition

PLoS Genetics ◽  
2021 ◽  
Vol 17 (2) ◽  
pp. e1009387
Author(s):  
Gediminas Drabavicius ◽  
Dirk Daelemans
Keyword(s):  
Pathogenic Bacteria ◽  
Biological Membrane ◽  
Cell Lysis ◽  
Cytolytic Activity ◽  
Asymmetric Distribution ◽  
Membrane Composition ◽  
Membrane Phospholipids ◽  
Knock Out ◽  
Target Membrane ◽  
Heparan Sulfates

Cholesterol-dependent cytolysins (CDCs), of which intermedilysin (ILY) is an archetypal member, are a group of pore-forming toxins secreted by a large variety of pathogenic bacteria. These toxins, secreted as soluble monomers, oligomerize upon interaction with cholesterol in the target membrane and transect it as pores of diameters of up to 100 to 300 Å. These pores disrupt cell membranes and result in cell lysis. The immune receptor CD59 is a well-established cellular factor required for intermedilysin pore formation. In this study, we applied genome-wide CRISPR-Cas9 knock-out screening to reveal additional cellular co-factors essential for ILY-mediated cell lysis. We discovered a plethora of genes previously not associated with ILY, many of which are important for membrane constitution. We show that heparan sulfates facilitate ILY activity, which can be inhibited by heparin. Furthermore, we identified hits in both protein and lipid glycosylation pathways and show a role for glucosylceramide, demonstrating that membrane organization is important for ILY activity. We also cross-validated identified genes with vaginolysin and pneumolysin and found that pneumolysin’s cytolytic activity strongly depends on the asymmetric distribution of membrane phospholipids. This study shows that membrane-targeting toxins combined with genetic screening can identify genes involved in biological membrane composition and metabolism.

QSCR Analysis of Cytotoxicity of 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones on Chinese Hamster Ovary Cell Line: Design of REPUBLIC1986

2021 ◽  
Vol 28 ◽  
Author(s):  
Shikha Joon ◽  
Rajeev K. Singla ◽  
Bairong Shen ◽  
Mohammad Amjad Kamal
Keyword(s):  
Cell Line ◽  
Antitumor Agents ◽  
De Novo ◽  
Human Cancer ◽  
Structural Parameters ◽  
Chinese Hamster ◽  
Ovary Cell ◽  
Contour Plot ◽  
Computer Assisted ◽  
Line Design

Background: 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones are promising antitumor agents with enormous data on their profound cytotoxic effects on the human cancer cell lines. Objectives: We sought to perform a Quantitative structure cytotoxicity relationship (QSCR) analysis of a series of previously reported fluoroquinolone analogues using computer-assisted multiple regression analysis and investigate the cytotoxicity-inducing structural parameters among these congeners. Methods: The dataset was segregated into training and test sets of 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones by using a random selection method embedded in Vlife MDS 4.6 software and subjected to QSCR analysis. Next, cross-validation of the generated QSCR models was performed along with the external test set prediction. Finally, the data was analyzed, and contour plots were developed to deduce the cytotoxicity-inducing structural parameters among these congeners using Minitab® software. Results: The validated QSCR model exhibited a statistically significant predictive value of 92.27 percent. Our QSCR model revealed a direct proportionality between hydrogen counts and cytotoxicity and exclusion of sulphur and nitrogen with lesser crowding of cyclopropyl rings in future potential 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-one analogues. Based on the QSCR model predictions and contour plot analysis, the de novo REPUBLIC1986 molecule provided the best hit with predicted IC50 (µM) of 0.45 against CHO cell line and is amenable to salt formation crucial for anti-ovarian cancer activity. Conclusion: These findings suggest the relevancy of the developed QSCR model in designing novel, potent, and safer anti-cancer drugs with 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones as seed compounds.

scholarly journals Cell-derived biomimetic nanoparticles as a novel drug delivery system for atherosclerosis: predecessors and perspectives

2020 ◽  
Vol 7 (4) ◽  
pp. 349-358
Author(s):  
Long Yang ◽  
Guangchao Zang ◽  
Jingwen Li ◽  
Xinyue Li ◽  
Yuanzhu Li ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Drug Delivery ◽  
Precision Medicine ◽  
Blood Circulation ◽  
Drug Delivery Systems ◽  
High Morbidity ◽  
Whole Cells ◽  
Biomimetic Nanoparticles ◽  
Novel Drug Delivery System ◽  
Novel Drug

Abstract Atherosclerosis is a key mechanism underlying the pathogenesis of cardiovascular disease, which is associated with high morbidity and mortality. In the field of precision medicine for the treatment of atherosclerosis, nanoparticle (NP)-mediated drug delivery systems have great potential, owing to their ability to release treatment locally. Cell-derived biomimetic NPs have attracted extensive attention at present due to their excellent targeting to atherosclerotic inflammatory sites, low immunogenicity and long blood circulation time. Here, we review the utility of cell-derived biomimetic NPs, including whole cells, cell membranes and extracellular vesicles, in the treatment of atherosclerosis.

scholarly journals ChoK-ing the Pathogenic Bacteria: Potential of Human Choline Kinase Inhibitors as Antimicrobial Agents

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Moad Khalifa ◽  
Ling Ling Few ◽  
Wei Cun See Too
Keyword(s):  
Cell Wall ◽  
Targeted Delivery ◽  
Pathogenic Bacteria ◽  
Antimicrobial Agents ◽  
Kinase Inhibitors ◽  
Amino Acid Sequences ◽  
Choline Kinase ◽  
Anticancer Properties ◽  
Wide Range ◽  
Catalytic Sites

Novel antimicrobial agents are crucial to combat antibiotic resistance in pathogenic bacteria. Choline kinase (ChoK) in bacteria catalyzes the synthesis of phosphorylcholine, which is subsequently incorporated into the cell wall or outer membrane. In certain species of bacteria, phosphorylcholine is also used to synthesize membrane phosphatidylcholine. Numerous human ChoK inhibitors (ChoKIs) have been synthesized and tested for anticancer properties. Inhibition of S. pneumoniae ChoK by human ChoKIs showed a promising effect by distorting the cell wall and retarded the growth of this pathogen. Comparison of amino acid sequences at the catalytic sites of putative choline kinases from pathogenic bacteria and human enzymes revealed striking sequence conservation that supports the potential application of currently available ChoKIs for inhibiting bacterial enzymes. We also propose the combined use of ChoKIs and nanoparticles for targeted delivery to the pathogen while shielding the human host from any possible side effects of the inhibitors. More research should focus on the verification of putative bacterial ChoK activities and the characterization of ChoKIs with active enzymes. In conclusion, the presence of ChoK in a wide range of pathogenic bacteria and the distinct function of this enzyme has made it an attractive drug target. This review highlighted the possibility of “choking” bacterial ChoKs by using human ChoKIs.

scholarly journals Pentraxins: Structure, Function, and Role in Inflammation

2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Terry W. Du Clos
Keyword(s):  
Pathogenic Bacteria ◽  
Horseshoe Crab ◽  
Specific Interaction ◽  
Acute Phase Reactant ◽  
Membrane Phospholipids ◽  
Calcium Dependent ◽  
Reactive Protein ◽  
Amyloid P ◽  
Small Nuclear Ribonucleoproteins ◽  
Recognition Molecule

The pentraxins are an ancient family of proteins with a unique architecture found as far back in evolution as the Horseshoe crab. In humans the two members of this family are C-reactive protein and serum amyloid P. Pentraxins are defined by their sequence homology, their pentameric structure and their calcium-dependent binding to their ligands. Pentraxins function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. They function as opsonins for pathogens through activation of the complement pathway and through binding to Fc gamma receptors. Pentraxins also recognize membrane phospholipids and nuclear components exposed on or released by damaged cells. CRP has a specific interaction with small nuclear ribonucleoproteins whereas SAP is a major recognition molecule for DNA, two nuclear autoantigens. Studies in autoimmune and inflammatory disease models suggest that pentraxins interact with macrophage Fc receptors to regulate the inflammatory response. Because CRP is a strong acute phase reactant it is widely used as a marker of inflammation and infection.

Fetal lung in organ culture. III. Comparison of dexamethasone, thyroxine, and methylxanthines

1980 ◽  
Vol 48 (5) ◽  
pp. 872-877 ◽  
Author(s):  
I. Gross ◽  
C. M. Wilson ◽  
L. D. Ingleson ◽  
A. Brehier ◽  
S. A. Rooney
Keyword(s):  
Glycogen Content ◽  
Fetal Lung ◽  
Choline Kinase ◽  
Small Decrease ◽  
Rat Lung ◽  
Phospholipid Synthesis ◽  
Membrane Phospholipids ◽  
Choline Incorporation ◽  
Fetal Rat ◽  
Fetal Rat Lung

Exposure of explants of fetal rat lung to dexamethasone, thyroxine, or the methylxanthines, aminophylline and caffeine, resulted in a significant increase in the rate of choline incorporation into all the choline-containing phospholipids. Dexamethasone, aminophylline, or caffeine treatment also resulted in an increase in the percentage of radioactivity from [3H]acetate in the surfactant-associated phospholipids, disaturated phosphatidylcholine, and phosphatidylglycerol and a corresponding decrease in the membrane phospholipids. Exposure to thyroxine had different effects. Only aminophylline and caffeine produced an increase in the rate of incorporation of acetate into phospholipid. Differences were also observed in the activities of enzymes of phospholipid synthesis. The activity of cholinephosphate cytidylyltransferase was increased by dexamethasone and that of choline kinase and lysolecithin acyltransferase by aminophylline. Thyroxine had no effect on any of the enzymes examined. All these agents produced a significant decrease in lung glycogen content and a small decrease in the protein-to-DNA ratio. These data indicate that corticosteroids, thyroxine, and the methylxanthines act directly on the fetal lung, but produce different effects and presumably act via different mechanisms.

scholarly journals Drug responses are conserved across patient-derived xenograft models of melanoma leading to identification of novel drug combination therapies

2019 ◽  
Vol 122 (5) ◽  
pp. 648-657 ◽  
Author(s):  
Ryan J. Ice ◽  
Michelle Chen ◽  
Max Sidorov ◽  
Tam Le Ho ◽  
Rinette W. L. Woo ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Antitumor Agents ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
Drug Combinations ◽  
Response To Therapy ◽  
Combination Therapies ◽  
Mek Inhibitors ◽  
Patient Derived Xenograft ◽  
Novel Drug

Abstract Background Patient-derived xenograft (PDX) mouse tumour models can predict response to therapy in patients. Predictions made from PDX cultures (PDXC) would allow for more rapid and comprehensive evaluation of potential treatment options for patients, including drug combinations. Methods We developed a PDX library of BRAF-mutant metastatic melanoma, and a high-throughput drug-screening (HTDS) platform utilising clinically relevant drug exposures. We then evaluated 34 antitumor agents across eight melanoma PDXCs, compared drug response to BRAF and MEK inhibitors alone or in combination with PDXC and the corresponding PDX, and investigated novel drug combinations targeting BRAF inhibitor-resistant melanoma. Results The concordance of cancer-driving mutations across patient, matched PDX and subsequent PDX generations increases as variant allele frequency (VAF) increases. There was a high correlation in the magnitude of response to BRAF and MEK inhibitors between PDXCs and corresponding PDXs. PDXCs and corresponding PDXs from metastatic melanoma patients that progressed on standard-of-care therapy demonstrated similar resistance patterns to BRAF and MEK inhibitor therapy. Importantly, HTDS identified novel drug combinations to target BRAF-resistant melanoma. Conclusions The biological consistency observed between PDXCs and PDXs suggests that PDXCs may allow for a rapid and comprehensive identification of treatments for aggressive cancers, including combination therapies.

Sign in / Sign up

Export Citation Format

Share Document