Small molecules in the treatment of COVID-19

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

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Defining diverse Spike-Receptor interactions involved in SARS-CoV-2 entry: Mechanisms and Therapeutic Opportunities

Virology, Journal Year: 2025, Volume and Issue: unknown, P. 110507 - 110507

Published: March 1, 2025

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped RNA virus that caused the Disease 2019 (COVID-19) pandemic. The SARS-CoV-2 Spike glycoprotein binds to angiotensin converting enzyme (ACE2) on host cells facilitate viral entry. However, presence of in nearly all human organs - including those with little or no ACE2 expression suggests involvement alternative receptors. Recent studies have identified several cellular proteins and molecules influence entry through ACE2-dependent, ACE2-independent, inhibitory mechanisms. In this review, we explore how these receptors were identified, their patterns roles entry, impact infection. Additionally, discuss therapeutic strategies aimed at disrupting virus-receptor interactions mitigate COVID-19 pathogenesis.

Language: Английский

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Single-molecule imaging reveals allosteric stimulation of SARS-CoV-2 spike receptor binding domain by host sialic acid

Science Advances, Journal Year: 2024, Volume and Issue: 10(29)

Published: July 17, 2024

Conformational dynamics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S) mediate exposure binding site for cellular receptor, angiotensin-converting enzyme (ACE2). The N-terminal domain (NTD) S binds terminal sialic acid (SA) moieties on cell surface, but functional role this interaction in virus entry is unknown. Here, we report that NTD-SA enhances both S-mediated attachment and ACE2 binding. Through single-molecule Förster resonance energy transfer imaging individual trimers, demonstrate SA to NTD allosterically shifts conformational equilibrium, favoring enhanced ACE2-binding site. Antibodies target block binding, which contributes their mechanism neutralization. These findings inform mechanisms activation at surface.

Language: Английский

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Vascular endothelial cell injury: causes, molecular mechanisms, and treatments

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 16, 2025

Vascular endothelial cells form a single layer of flat that line the inner surface blood vessels, extending from large vessels to microvasculature various organs. These are crucial metabolic and endocrine components body, playing vital roles in maintaining circulatory stability, regulating vascular tone, preventing coagulation thrombosis. Endothelial cell injury is regarded as pivotal initiating factor pathogenesis diseases, triggered by multiple factors, including infection, inflammation, hemodynamic changes, which significantly compromise integrity function. This review examines causes, underlying molecular mechanisms, potential therapeutic approaches for injury, focusing specifically on damage cardiac ischemia/reperfusion (I/R) sepsis, diabetes. It delves into intricate signaling pathways involved emphasizing oxidative stress, mitochondrial dysfunction, inflammatory mediators, barrier damage. Current treatment strategies-ranging pharmacological interventions regenerative lifestyle modifications-face ongoing challenges limitations. Overall, this highlights importance understanding within context diseases necessity innovative methods improve patient outcomes.

Language: Английский

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A Comparison of Conserved Features in the Human Coronavirus Family Shows That Studies of Viruses Less Pathogenic than SARS-CoV-2, Such as HCoV-OC43, Are Good Model Systems for Elucidating Basic Mechanisms of Infection and Replication in Standard Laboratories

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 256 - 256

Published: Feb. 13, 2025

In 2021, at the height of COVID-19 pandemic, coronavirus research spiked, with over 83,000 original articles related to word "coronavirus" added online resource PubMed. Just 2 years later, in 2023, only 30,900 were added. While, irrefutably, funding drastically decreased, a possible explanation for decrease interest is that projects on SARS-CoV-2, causative agent COVID-19, halted due challenge establishing good cellular or animal model system. Most laboratories do not have capabilities culture SARS-CoV-2 'in house' as this requires Biosafety Level (BSL) 3 laboratory. Until recently, BSL laboratory endemic coronaviruses was arduous low cytopathic effect isolated cell infection models and lack means quantify viral loads. The purpose review article compare human provide an assessment latest techniques use coronaviruses-HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1-as lower-biosafety-risk more pathogenic coronaviruses-SARS-CoV-2, SARS-CoV, MERS-CoV.

Language: Английский

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SARS-CoV-2 Spike N-Terminal Domain Engages 9-O-Acetylated α2–8-Linked Sialic Acids

ACS Chemical Biology, Journal Year: 2023, Volume and Issue: 18(5), P. 1180 - 1191

Published: April 27, 2023

SARS-CoV-2 viruses engage ACE2 as a functional receptor with their spike protein. The S1 domain of the protein contains C-terminal binding (RBD) and an N-terminal (NTD). NTD other coronaviruses includes glycan cleft. However, for NTD, protein–glycan was only observed weakly sialic acids highly sensitive methods. Amino acid changes in variants concern (VoC) show antigenic pressure, which can be indication NTD-mediated binding. Trimeric proteins SARS-CoV-2, alpha, beta, delta, omicron did not reveal capability. Unexpectedly, beta subvariant strain (501Y.V2-1) to Vero E6 cells sialidase pretreatment. Glycan microarray analyses identified putative 9-O-acetylated ligand, confirmed by catch-and-release ESI-MS, STD-NMR analyses, graphene-based electrochemical sensor. variant attained enhanced modality specificity toward structures, suggesting dual-receptor functionality domain, quickly selected against. These results indicate that probe additional evolutionary space, allowing receptors on surface target cells.

Language: Английский

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Proton- versus Cation-Selective Transport of Saccharide Rim-Appended Pillar[5]arene Artificial Water Channels

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(40), P. 21904 - 21914

Published: Sept. 28, 2023

Transport of water across cell membranes is a fundamental process for important biological functions. Herein, we focused our research on new type symmetrical saccharide rim-functionalized pillar[5]arene (PA-S) artificial channels with variable pore structures. To point out the versatility PA-S channels, systematically varied nature anchoring/gate keepers d-mannoside, d-mannuronic acid, or sialic acid H-bonding groups lateral (PA) arms, known as good membrane adhesives, to best describe influence chemical structure their transport activity. The control hydrophobic binding-hydrophilic binding balance an feature influencing channels' structuration and efficiency proper insertion into bilayer membranes. glycosylated PA performances were assessed in lipid membranes, able at high rates (∼106-107 waters/s/channel within 1 order magnitude aquaporins), serving selective proton railways total Na+ K+ rejection. Molecular simulation substantiates idea that PAs can generate supramolecular pores, featuring hydrophilic carbohydrate gate-keepers serve water-sponge relays channel entrance, effectively absorbing redirecting channel. present may be regarded rare biomimetic example presenting vs cation selectivity performances.

Language: Английский

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Disruption Mechanisms of Enveloped Viruses by Ionic and Nonionic Surfactants

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(3), P. 768 - 780

Published: Jan. 16, 2024

The world has witnessed multiple pandemics and endemics caused by enveloped viruses in the past century. To name a few, ongoing COVID-19 pandemic other pandemics/endemics coronaviruses, influenza viruses, HIV-1, etc. external topical applications of surfactants have been effective limiting spread viruses. While it is well-known that inactivate virus particles (virions), mechanism action against virions not yet established. In this work, we evaluated surfactant-induced disruption cocktail containing mumps, measles, rubella We applied total internal reflection fluorescence microscopy technique to trace temporal changes signal from single upon addition surfactant solution. report solubilize either viral lipid membrane, proteins, or both. Ionic surfactants, depending on their charge interaction type with lipids can cause bursting perforation envelope, whereas nonionic symmetric expansion envelope concentration.

Language: Английский

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SARS-CoV-2 Binding to Terminal Sialic Acid of Gangliosides Embedded in Lipid Membranes

ACS Infectious Diseases, Journal Year: 2023, Volume and Issue: 9(7), P. 1346 - 1361

Published: May 5, 2023

Multiple recent reports indicate that the S protein of SARS-CoV-2 specifically interacts with membrane receptors and attachment factors other than ACE2. They likely have an active role in cellular entry virus. In this article, we examined binding particles to gangliosides embedded supported lipid bilayers (SLBs), mimicking cell membrane-like environment. We show virus binds sialylated (sialic acid (SIA)) gangliosides, i.e., GD1a, GM3, GM1, as determined from acquired single-particle fluorescence images using a time-lapse total internal reflection (TIRF) microscope. The data events, apparent rate constant, maximum coverage on ganglioside-rich SLBs higher affinity toward GD1a GM3 compared GM1 ganglioside. Enzymatic hydrolysis SIA–Gal bond confirms SIA sugar unit is essential for even surface sialic critical structural difference between GM3/GD1a presence at main or branched chain. conclude number per ganglioside can weakly influence initial particles, whereas terminal more exposed SLBs.

Language: Английский

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Identification and Comparison of the Sialic Acid-Binding Domain Characteristics of Avian Coronavirus Infectious Bronchitis Virus Spike Protein

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(5)

Published: April 25, 2023

Infectious bronchitis virus (IBV) infections are initiated by the transmembrane spike (S) glycoprotein, which binds to host factors and fuses viral cell membranes. The N-terminal domain of S1 subunit IBV S protein sialic acids, but precise location acid binding (SABD) role SABD in IBV-infected chickens remain unclear. Here, we identify amino (aa) residues 19 227 (209 aa total) strains SD (GI-19) GD (GI-7), corresponding region M41 (GI-1), as minimal using truncated histochemistry neuraminidase assays. Both α-2,3- α-2,6-linked acids on surfaces CEK cells can be used attachment receptors IBV, leading increased infection efficiency. However, 9-O acetylation glycerol side chain inhibits binding. We further constructed recombinant gene or genomes were replaced with from reverse genetics. Infecting these viruses revealed that virulence nephrotropism rSDM41-S1, rSDM41-206, rGDM41-S1, rGDM41-206 decreased various degrees compared their parental strains. A positive sera cross-neutralization test showed serotypes changed for viruses. Our results provide insight into may aid vaccine design. IMPORTANCE To date, only α-2,3-linked has been identified a potential receptor IBV. show minimum constituting characteristics (GI-19), (GI-1) acids. modification partially acid, while also bind molecules linked through an α-2,6 linkage, serving another determinant. Substitution putative strain resulted reduced virulence, nephrotropism, serotype switch. These findings suggest diversified during evolution γ-coronaviruses, impacting biological properties offer mechanisms invades cells.

Language: Английский

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