Vitamin K – sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity

Nutrition Reviews, Journal Year: 2021, Volume and Issue: 80(4), P. 677 - 698

Published: July 9, 2021

Abstract Vitamin K is traditionally connected with blood coagulation, since it needed for the posttranslational modification of 7 proteins involved in this cascade. However, also maturation another 11 or 12 that play different roles, encompassing particular modulation calcification connective tissues. Since process physiologically bones, but pathological arteries, a great deal research has been devoted to finding possible link between vitamin and prevention osteoporosis cardiovascular diseases. Unfortunately, current knowledge does not allow us make decisive conclusion about such link. One explanation diversity biological activity K, which single compound general term covering natural plant animal forms (K1 K2) as well their synthetic congeners (K3 K4). K1 (phylloquinone) found several vegetables. Menaquinones (MK4–MK13, series compounds known are mostly bacterial origin introduced into human diet mainly through fermented cheeses. Current kinetics detection, toxicity discussed review.

Language: Английский

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Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike–ACE2 Interaction

ACS Central Science, Journal Year: 2022, Volume and Issue: 8(5), P. 527 - 545

Published: March 29, 2022

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as coreceptor with the ACE2 protein for S1 spike on SARS-CoV-2 virus, providing tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have anticoagulant and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), cancer drug candidate, binds destabilizes receptor binding domain directly inhibits its to ACE2, consistent molecular modeling identification of multiple contacts overlapping sites. Assays clinical isolates virus potently infection monkey Vero E6 cells physiologically relevant human bronchial epithelial at safe concentrations. Pixatimod also retained broad potency against variants concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.1.529 (Omicron). Furthermore, in K18-hACE2 mouse model, significantly reduced viral titers upper respiratory tract virus-induced weight loss. This demonstration potent anti-SARS-CoV-2 tolerant emerging mutations establishes proof-of-concept targeting HS-Spike protein-ACE2 axis mimetics provides strong rationale investigation potential multimodal COVID-19.

Language: Английский

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Association of vitamin D status with COVID-19 and its severity

Reviews in Endocrine and Metabolic Disorders, Journal Year: 2022, Volume and Issue: 23(3), P. 579 - 599

Published: Jan. 4, 2022

Language: Английский

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Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS‐CoV‐2 Spike Protein**

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(13), P. 7098 - 7110

Published: Jan. 20, 2021

Abstract We investigate binding of linoleate and other potential ligands to the recently discovered fatty acid site in SARS‐CoV‐2 spike protein, using docking molecular dynamics simulations. Simulations suggest that dexamethasone stabilize locked conformation, thus reducing opportunity for ACE2 interaction. In contrast, cholesterol may expose receptor‐binding domain by destabilizing closed structure, preferentially a different hinge region open structure. docked library FDA‐approved drugs an approach reproduces structure complex. Docking identifies steroids (including vitamin D); retinoids (some known be active vitro, A); K as conformation. The bind diverse array ligands, including dietary components, therefore provides promising target therapeutics or prophylaxis.

Language: Английский

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Accelerating COVID-19 Research Using Molecular Dynamics Simulation

The Journal of Physical Chemistry B, Journal Year: 2021, Volume and Issue: 125(32), P. 9078 - 9091

Published: July 28, 2021

The COVID-19 pandemic has emerged as a global medico-socio-economic disaster. Given the lack of effective therapeutics against SARS-CoV-2, scientists are racing to disseminate suggestions for rapidly deployable therapeutic options, including drug repurposing and repositioning strategies. Molecular dynamics (MD) simulations have provided opportunity make rational scientific breakthroughs in time crisis. Advancements these technologies recent years become an indispensable tool studying protein structure, function, dynamics, interactions, discovery. Integrating structural data obtained from high-resolution methods with MD helped comprehending process infection pathogenesis, well SARS-CoV-2 maturation host cells, short duration time. It also guided us identify prioritize targets new chemical entities, repurpose drugs. Here, we discuss how simulation been explored by community accelerate guide translational research on past year. We considered future directions researchers, where can help fill existing gaps research.

Language: Английский

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A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors

Biophysical Journal, Journal Year: 2021, Volume and Issue: 120(6), P. 983 - 993

Published: Feb. 18, 2021

Language: Английский

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Rationally Controlling Selective Steroid Hydroxylation via Scaffold Sampling of a P450 Family

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(2), P. 1280 - 1289

Published: Jan. 6, 2023

Many steroids are important pharmaceutically active compounds, while cytochrome P450 monooxygenases (CYPs) attractive enzymes for applications in steroidal drug synthesis. However, the catalytic efficiency of existing P450s is not routinely high enough, as well molecular basis selectivity control unclear, which severely restrict their real applications. Here, a 16β steroid-hydroxylase CYP109B4 from Bacillus sonorensis identified with excellent and activity. The crystallization structural analysis reveal potential three "hotspot" residues (V84, V292, S387) responsible control. Then, guided by sequence–function relationships revealed mutability landscape construction on residues, focused rational iterative site-specific mutagenesis (FRISM) limited saturation were performed, provide variant B4-M7 (L240V/S387F/V84L/V292S/I291T/M290F/F294I) completely switched regioselectivity to 15β. subsequent computational uncovers insights into substrate binding modes its variants, further confirms critical role Finally, generality conserved-"hotspots"-mediated demonstrated performing scaffold sampling between panel CYP109B members. Overall, addition present chemical results, our study provides guidance rationally designing more biocatalysts practical (industrial)

Language: Английский

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Focused rational iterative site-specific mutagenesis (FRISM): A powerful method for enzyme engineering

Molecular Catalysis, Journal Year: 2023, Volume and Issue: 553, P. 113755 - 113755

Published: Dec. 9, 2023

Language: Английский

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A Reflection on the Use of Molecular Simulation to Respond to SARS-CoV-2 Pandemic Threats

The Journal of Physical Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 3249 - 3263

Published: March 21, 2025

Molecular simulations play important roles in understanding the lifecycle of SARS-CoV-2 virus and contribute to design development antiviral agents diagnostic tests for COVID. Here, we discuss insights that such have provided challenges involved, focusing on main protease (Mpro) spike glycoprotein. Mpro is leading target antivirals, while glycoprotein vaccine design. Finally, reflect lessons from this pandemic simulation community. Data sharing initiatives collaborations across international research community contributed advancing knowledge should be built help future pandemics other global as antimicrobial resistance.

Language: Английский

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Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 11, 2022

Abstract As the global burden of SARS-CoV-2 infections escalates, so does evolution viral variants with increased transmissibility and pathology. In addition to this entrenched diversity, RNA viruses can also display genetic diversity within single infected hosts co-existing evolving differently in distinct cell types. The BriSΔ variant, originally identified as a subpopulation from isolate hCoV-19/England/02/2020, comprises spike an eight amino-acid deletion encompassing furin recognition motif S1/S2 cleavage site. We elucidate structure, function molecular dynamics providing mechanistic insight into how correlates tropism, ACE2 receptor binding infectivity variant. Our results reveal long-range allosteric communication between functional domains that differ wild-type variant support view probing multiple evolutionary trajectories types same host.

Language: Английский

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