Amyloidogenesis of SARS-CoV-2 Spike Protein

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(20), P. 8945 - 8950

Published: May 17, 2022

SARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities amyloid-disease blood coagulation and fibrinolytic disturbances together neurologic cardiac problems led us to investigate the amyloidogenicity spike protein (S-protein). Amyloid fibril assays peptide library mixtures theoretical predictions identified seven amyloidogenic sequences within S-protein. All peptides in isolation formed aggregates during incubation at 37 °C. Three 20-amino acid long synthetic (sequence 192–211, 601–620, 1166–1185) fulfilled three amyloid criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity, ultrastructural fibrillar morphology. Full-length folded S-protein did not form fibrils, but amyloid-like fibrils evident branching were 24 h coincubation protease neutrophil elastase (NE) vitro. NE efficiently cleaved S-protein, rendering exposure segments accumulation 194–203, part most peptide. overexpressed inflamed sites viral infection. Our data propose molecular mechanism for potential amyloidogenesis humans facilitated endoproteolysis. The prospective COVID-19 disease pathogenesis can be important understanding COVID-19.

Language: Английский

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Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation

ACS Chemical Neuroscience, Journal Year: 2021, Volume and Issue: 13(1), P. 143 - 150

Published: Dec. 3, 2021

First cases that point at a correlation between SARS-CoV-2 infections and the development of Parkinson's disease (PD) have been reported. Currently, it is unclear if there also direct causal link these diseases. To obtain first insights into possible molecular relation viral aggregation α-synuclein protein amyloid fibrils characteristic for PD, we investigated effect presence proteins on aggregation. We show, in test tube experiments, spike (S-protein) has no aggregation, while nucleocapsid (N-protein) considerably speeds up process. observe formation multiprotein complexes eventually fibrils. Microinjection N-protein SH-SY5Y cells disturbed proteostasis increased cell death. Our results toward interactions as basis observed Parkinsonism.

Language: Английский

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‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA

Biomedicines, Journal Year: 2023, Volume and Issue: 11(8), P. 2287 - 2287

Published: Aug. 17, 2023

The COVID-19 pandemic caused much illness, many deaths, and profound disruption to society. production of ‘safe effective’ vaccines was a key public health target. Sadly, unprecedented high rates adverse events have overshadowed the benefits. This two-part narrative review presents evidence for widespread harms novel product mRNA adenovectorDNA is in attempting provide thorough overview arising from new technology that relied on human cells producing foreign antigen has pathogenicity. first paper explores peer-reviewed data counter attached these technologies. Spike protein pathogenicity, termed ‘spikeopathy’, whether SARS-CoV-2 virus or produced by vaccine gene codes, akin ‘synthetic virus’, increasingly understood terms molecular biology pathophysiology. Pharmacokinetic transfection through body tissues distant injection site lipid-nanoparticles viral-vector carriers means ‘spikeopathy’ can affect organs. inflammatory properties nanoparticles used ferry mRNA; N1-methylpseudouridine employed prolong synthetic function; biodistribution DNA codes translated spike proteins, autoimmunity via contribute harmful effects. reviews autoimmune, cardiovascular, neurological, potential oncological effects, autopsy spikeopathy. With gene-based therapeutic technologies planned, re-evaluation necessary timely.

Language: Английский

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Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(13), P. 11287 - 11368

Published: May 20, 2022

Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus-host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component combating disease 2019 (COVID-19) due to their low cost, efficiency, fact that they are free from safety ethical constraints. Additionally, mechanism governs global transmission SARS-CoV-2 cannot be revealed individual experiments was discovered by integrating genotyping massive viral sequences, biophysical modeling protein-protein deep mutational data, learning, advanced mathematics. There exists a tsunami literature on molecular modeling, simulations, predictions related developments drugs, vaccines, antibodies, diagnostics. To provide readers with quick update about this literature, we present comprehensive systematic methodology-centered review. Aspects such as biophysics, bioinformatics, cheminformatics, machine mathematics discussed. review will beneficial researchers who looking ways contribute those interested status field.

Language: Английский

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SARS-CoV-2 Proteins Interact with Alpha Synuclein and Induce Lewy Body-like Pathology In Vitro

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(6), P. 3394 - 3394

Published: March 21, 2022

Growing cases of patients reported have shown a potential relationship between (severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 infection and Parkinson's disease (PD). However, it is unclear whether there molecular link these two diseases. Alpha-synuclein (α-Syn), an aggregation-prone protein, considered crucial factor in PD pathology. In this study, bioinformatics analysis confirmed favorable binding affinity α-Syn spike (S) protein nucleocapsid (N) direct interactions were further verified HEK293 cells. The expression was upregulated its aggregation accelerated by S N protein. It noticed that proteins caused Lewy-like pathology the presence overexpression. By confirming directly interact with α-Syn, our study offered new insights into mechanism underlying development on background COVID-19.

Language: Английский

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Current Evidence in SARS-CoV-2 mRNA Vaccines and Post-Vaccination Adverse Reports: Knowns and Unknowns

Diagnostics, Journal Year: 2022, Volume and Issue: 12(7), P. 1555 - 1555

Published: June 26, 2022

The novel mRNA vaccinations against COVID-19 are gaining worldwide attention for their potential efficacy, as well the diagnosis of some post-vaccination-reported adverse reactions. In this state-of-the-art review article, we present current evidence regarding mainly spontaneous allergic reactions, skin occurrences, vascular, blood, endocrine and heart events, respiratory reports, gastrointestinal, hepatic kidney reproductive pregnancy issues muscle ear, eye, neurologic psychiatric events following vaccination COVID-19. We further strategies, provide important information side effects associated with spike protein based LNP-mRNA vaccine its adjuvants, all possible dangerous roles protein, discuss our expert opinion on knowns unknowns towards topic.

Language: Английский

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Long-Term Effects of SARS-CoV-2 in the Brain: Clinical Consequences and Molecular Mechanisms

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(9), P. 3190 - 3190

Published: April 28, 2023

Numerous investigations have demonstrated significant and long-lasting neurological manifestations of COVID-19. It has been suggested that as many four out five patients who sustained COVID-19 will show one or several symptoms can last months after the infection run its course. Neurological are most common in people less than 60 years age, while encephalopathy is more those over 60. Biological mechanisms for these need to be investigated may include both direct indirect effects virus on brain spinal cord. Individuals with Alzheimer’s disease (AD) related dementia, well persons Down syndrome (DS), especially vulnerable COVID-19, but biological reasons this not clear. Investigating consequences an urgent emerging medical need, since close 700 million worldwide now had at least once. likely there a new burden healthcare economy dealing long-term severe SARS-CoV-2 infections long COVID, even younger generations. Interestingly, acute strikingly similar observed mild traumatic injury (mTBI) concussion, including dizziness, balance issues, anosmia, headaches. The possible convergence pathways involved discussed. current review focused commonly described symptoms, molecular involved.

Language: Английский

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Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 123 - 123

Published: Jan. 9, 2024

The COVID-19 pandemic has brought to the forefront intricate relationship between SARS-CoV-2 and its impact on neurological complications, including potential links neurodegenerative processes, characterized by a dysfunction of protein quality control systems ER stress. This review article explores role systems, such as Unfolded Protein Response (UPR), Endoplasmic Reticulum-Associated Degradation (ERAD), Ubiquitin–Proteasome System (UPS), autophagy molecular chaperones, in infection. Our hypothesis suggests that produces stress exploits leading disruption proteostasis cannot be solved host cell. culminates cell death may represent link neurodegeneration.

Language: Английский

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The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(15), P. 8226 - 8226

Published: July 30, 2021

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s (AD), major form dementia, β-amyloid (Aβ) levels in blood increased; however, impact elevated Aβ on progression COVID-19 remains largely unknown. Here, our findings demonstrate Aβ1-42, but not Aβ1-40, bound various viral proteins a preferentially high affinity for spike protein S1 subunit (S1) acute respiratory syndrome 2 (SARS-CoV-2) and receptor, angiotensin-converting enzyme (ACE2). These bindings were mainly through C-terminal residues Aβ1-42. Furthermore, Aβ1-42 strengthened binding SARS-CoV-2 ACE2 increased entry production IL-6 pseudovirus infection model. Intriguingly, data from surrogate mouse model intravenous inoculation show clearance was dampened presence extracellular domain trimers SARS-CoV-2, whose effects can be prevented by novel anti-Aβ antibody. conclusion, these suggest may have negative course severity infection. Further investigations warranted elucidate underlying mechanisms examine whether reducing level is beneficial fight against AD.

Language: Английский

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Creutzfeldt-Jakob disease after COVID-19: infection-induced prion protein misfolding? A case report

Prion, Journal Year: 2022, Volume and Issue: 16(1), P. 78 - 83

Published: July 3, 2022

Creutzfeldt-Jakob disease (CJD) is a rare, fatal presenting with rapidly progressive neurological deficits caused by the accumulation of misfolded form (PrPSc) prion protein (PrPc). Coronavirus 2019 (COVID-19) primarily respiratory syndrome severe acute coronavirus 2 (SARS-CoV-2); many diverse complications have been observed after COVID-19. We describe young patient developing CJD two months mild Presenting symptoms were visuospatial and ataxia, evolving into bedridden state preserved consciousness diffuse myoclonus. Diagnostic work-up was suggestive CJD. The early age onset short interval between might suggest causal relationship: COVID-19-related neuroinflammatory may induced misfolding subsequent aggregation PrPSc. present case emphasizes link neuroinflammation misfolding. Further studies are needed to establish role SARS-CoV-2 as an initiator neurodegeneration.

Language: Английский

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