The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour

Computational and Structural Biotechnology Journal, Journal Year: 2021, Volume and Issue: 20, P. 139 - 147

Published: Dec. 11, 2021

The SARS-CoV-2 spike protein is the first contact point between virus and host cells mediates membrane fusion. Recently, a fatty acid binding site was identified in (Toelzer

Language: Английский

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Disorders of the Cholinergic System in COVID-19 Era—A Review of the Latest Research

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(2), P. 672 - 672

Published: Jan. 8, 2022

The appearance of the SARS-CoV-2 virus initiated many studies on effects human body. So far, its negative influence functioning morphological and physiological units, including nervous system, has been demonstrated. Consequently, research conducted changes that may cause in cholinergic system. aim this study is to review latest from years 2020/2021 regarding disorders system caused by virus. As a result research, it was found presence COVID-19 disrupts activity for example, causing development myasthenia gravis or change acetylcholine activity. spike protein sequence similar neurotoxins, capable binding nicotinic receptors (nAChR). This be proof can bind nAChR. Nicotine caffeine have structures antiviral drugs, angiotensin-converting enzyme 2 (ACE 2) epitopes are recognized SARS-CoV-2, with potential inhibit formation ACE 2/SARS-CoV-2 complex. blocking enhanced when nicotine used together drugs. nAChR agonists along drugs therapy. result, possible develop therapies use these compounds reduce cytokine production. Another promising therapy non-invasive stimulation vagus nerve, which soothes body's storm. Research an area should continue developed as there need further research. It firmly stated causes dysregulation leads because will prevent receptor. There both vitro vivo. noted connection virus, might dependencies solutions.

Language: Английский

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A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor

Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 59(10), P. 6076 - 6090

Published: July 20, 2022

Language: Английский

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Dynamical nonequilibrium molecular dynamics simulations reveal allosteric networks, signal transduction mechanisms, and sites associated with drug resistance in biomolecular systems

Molecular Physics, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 16, 2024

Language: Английский

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Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?

Bioelectronic Medicine, Journal Year: 2023, Volume and Issue: 9(1)

Published: Jan. 18, 2023

Following a SARS-CoV-2 infection, many individuals suffer from post-COVID-19 syndrome. It makes them unable to proceed with common everyday activities due weakness, memory lapses, pain, dyspnea and other unspecific physical complaints. Several investigators could demonstrate that the related spike glycoprotein (SGP) attaches not only ACE-2 receptors but also shows DNA sections highly affine nicotinic acetylcholine (nAChRs). The nAChR is principal structure of cholinergic neuromodulation responsible for coordinated neuronal network interaction. Non-intrinsic viral attachment compromises integrative interneuronal communication substantially. This explains cognitive, neuromuscular mood impairment, as well vegetative symptoms, characterizing agonist ligand nicotine an up 30-fold higher affinity nACHRs than (ACh). We therefore hypothesize this molecule displace virus pave way unimpaired signal transmission. Treating several suffering syndrome patch application, we witnessed improvements ranging immediate substantial complete remission in matter days.

Language: Английский

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SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid

Journal of Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 15(3)

Published: March 1, 2023

Abstract The SARS-CoV-2 spike protein contains a functionally important fatty acid (FA) binding site, which is also found in some other coronaviruses, e.g. SARS-CoV and MERS-CoV. occupancy of the FA site by linoleic (LA) reduces infectivity ‘locking’ less infectious conformation. Here, we use dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations to compare allosteric responses variants LA removal. D-NEMD show that coupled functional regions protein, receptor-binding motif (RBM), N-terminal domain (NTD), furin cleavage surrounding fusion peptide. identify networks connecting these regions. comparison between wild-type four (Alpha, Delta, Delta plus, Omicron BA.1) shows differ significantly their connections on Alpha are generally similar those with exception RBM S71–R78 region, weaker link site. In contrast, most different variant, exhibiting significant differences RBM, NTD, V622–L629, These modulation may be relevance, potentially affecting transmissibility virulence. Experimental effects variants, including emerging warranted.

Language: Английский

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SARS-CoV-2 Spike Protein Downregulates Cell Surface α7nAChR through a Helical Motif in the Spike Neck

ACS Chemical Neuroscience, Journal Year: 2023, Volume and Issue: 14(4), P. 689 - 698

Published: Feb. 6, 2023

A deficiency of the functional α7 nicotinic acetylcholine receptor (α7nAChR) impairs neuronal and immune systems. The SARS-CoV-2 spike protein (S12) facilitates virus cell entry during COVID-19 infection can also independently disrupt cellular functions. Here, we found that S12 expression significantly downregulated surface α7nAChR in mammalian cells. helical segment (L1145-L1152) neck was identified to be responsible for downregulation α7nAChR, as mutant

Language: Английский

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Immunogenicity and safety study of a single dose of SpikoGen® vaccine as a heterologous or homologous intramuscular booster following a primary course of mRNA, adenoviral vector or recombinant protein COVID-19 vaccine in ambulatory adults

Vaccine, Journal Year: 2025, Volume and Issue: 49, P. 126744 - 126744

Published: Feb. 5, 2025

Language: Английский

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Long COVID – a critical disruption of cholinergic neurotransmission?

Bioelectronic Medicine, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 27, 2025

Abstract Background Following the COVID-19 pandemic, there are many chronically ill Long COVID (LC) patients with different symptoms of varying degrees severity. The pathological pathways LC remain unclear until recently and make identification path mechanisms exploration therapeutic options an urgent challenge. There is apparent relationship between impaired cholinergic neurotransmission. Methods This paper reviews current literature on effects blocked nicotinic acetylcholine receptors (nAChRs) main affected organ cell systems contrasts this unblocking alkaloid nicotine. In addition, presented that could explain previously unexplained phenomenon post-vaccination syndrome (PVS). fact not only SARS-CoV-2 but numerous other viruses can bind to nAChRs discussed under assumption post-viral diseases autoimmune (ADs) may also be due transmission. We present a case report demonstrates changes in transmission, specifically, availability α4β2 by using (-)-[ 18 F]Flubatine whole-body positron emission tomography (PET) imaging dysfunction patient along significant neurological improvement before after low-dose transcutaneous nicotine (LDTN) administration. Lastly, descriptive analysis evaluation were conducted results survey involving 231 users LDTN. Results A substantial body research has emerged offers compelling explanation for LC, suggesting it plausibly explained because nAChR function human body. ten-day course administration, no enduring neuropathological manifestations observed patient. observation was accompanied increase number free ligand binding sites (LBS) nAChRs, as determined PET imaging. shows majority (73.5%) their LC/MEF/CFS disease result Conclusions conclusion, based knowledge, LDTN appears promising safe procedure relieve expected long-term harm.

Language: Английский

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Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike

Published: March 11, 2025

The trimeric spike protein plays an essential role in the SARS-CoV-2 virus lifecycle, facilitating entry through binding to cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediating viral-host membrane fusion. contains a fatty acid (FA) site at interface between two neighbouring receptor-binding domains. This site, also found some other coronaviruses, binds free acids such as linoleic acid. Binding this locks non-infectious, closed conformation. is coupled functionally important regions, but effects of glycans on these allosteric have not been investigated. Understanding allostery how modulates behaviour could potentiate development promising alternative strategies for new coronavirus therapies. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations investigate FA fully glycosylated original ancestral variant. results show networks that connect functional regions protein, including more than 40 Å away, motif, antigenic supersite N-terminal domain, furin cleavage surrounding fusion peptide, another known bind heme biliverdin. identified here highlight complexity modulation reveal striking unexpected connection different sites. Notably, 65% amino substitutions, deletions insertions Alpha, Beta, Delta, Gamma Omicron variants map onto or close pathways. Comparison connections from D-NEMD non-glycosylated spikes revealed presence does qualitatively change internal pathways within with transmission structural changes subunits.

Language: Английский

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