C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(12)

Published: April 27, 2023

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved pathophysiology. signaling increased locally lung, especially neutrophils of critically ill patients compared influenza infection, as well lung tissue K18-hACE2 Tg mice (Tg mice) infected SARS-CoV-2. Genetic pharmacological inhibition C5aR1 ameliorated immunopathology Tg-infected mice. Mechanistically, found drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm role indicate antagonists useful for treatment.

Language: Английский

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Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

ACS Omega, Journal Year: 2023, Volume and Issue: 8(25), P. 22603 - 22612

Published: June 14, 2023

There are very few small-molecule antivirals for SARS-CoV-2 that either currently approved (or emergency authorized) in the US or globally, including remdesivir, molnupiravir, and paxlovid. The increasing number of variants have appeared since outbreak began over three years ago raises need continual development updated vaccines orally available order to fully protect treat population. viral main protease (Mpro) papain-like (PLpro) key replication; therefore, they represent valuable targets antiviral therapy. We herein describe an vitro screen performed using 2560 compounds from Microsource Spectrum library against Mpro PLpro attempt identify additional hits could be repurposed SARS-CoV-2. subsequently identified 2 8 PLpro. One these was quaternary ammonium compound cetylpyridinium chloride with dual activity (IC50 = 2.72 ± 0.09 μM IC50 7.25 0.15 Mpro). A second inhibitor selective estrogen receptor modulator raloxifene 3.28 0.29 42.8 6.7 additionally tested several kinase inhibitors olmutinib 0.54 0.04 μM), bosutinib 4.23 0.28 crizotinib 3.81 dacominitinib 3.33 0.06 μM) as first time. In some cases, molecules also been by others this virus, we used Calu-3 cells infected results suggest drugs can promising proteases, cases validated their activity. identification known targeting may provide new repurposing opportunities starting points chemical optimization.

Language: Английский

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Repurposing High-Throughput Screening Reveals Unconventional Drugs with Antimicrobial and Antibiofilm Potential Against Methicillin-Resistant Staphylococcus aureus from a Cystic Fibrosis Patient

Antibiotics, Journal Year: 2025, Volume and Issue: 14(4), P. 402 - 402

Published: April 14, 2025

Background/Objectives: Antibiotic therapy faces challenges from rising acquired and biofilm-related antibiotic resistance rates. High levels to commonly used antibiotics have been observed in methicillin-resistant Staphylococcus aureus (MRSA) strains among cystic fibrosis (CF) patients, indicating an urgent need for new antibacterial agents. This study aimed identify potential novel therapeutics with antibiofilm activities against MRSA CF strain by screening, the first time, Drug Repurposing Compound Library (MedChem Express). Methods/Results: Among 3386 compounds, a high-throughput screening-based spectrophotometric approach identified 2439 (72%), 654 (19.3%), 426 (12.6%) drugs active planktonic cells, biofilm formation, preformed biofilm, respectively, although different extents. The most hits were 193 (5.7%), causing 100% growth inhibition; 5 (0.14%), excellent activity formation (i.e., reduction ≥ 90%); 4, showing high 60% ≤ < 90%) biofilms. belonged several primary research areas, “cancer” being prevalent. After performing literature review other, already published biological properties that could be relevant lung environment other pathogens, anti-inflammatory anti-virulence potential), interesting following: 5-(N,N-Hexamethylene)-amiloride (diuretic), Toremifene (anticancer), Zafirlukast (antiasthmatic), Fenretide Montelukast (antiasthmatic) S. cells; Hemin formation; Heparin, Clemastine (antihistaminic), Bromfenac (nonsteroidal anti-inflammatory) established Conclusions: These findings warrant further vitro vivo studies confirm of repurposing these compounds managing infections caused patients.

Language: Английский

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A mimetic peptide of ACE2 protects against SARS-CoV-2 infection and decreases pulmonary inflammation related to COVID-19

Antiviral Research, Journal Year: 2024, Volume and Issue: 229, P. 105968 - 105968

Published: July 14, 2024

Language: Английский

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Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

Viruses, Journal Year: 2023, Volume and Issue: 15(2), P. 568 - 568

Published: Feb. 19, 2023

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, existing antivirals suffer from major limitations regarding drug resistance a limited spectrum activity. In fact, approved directly acting antiviral (DAA) drugs, which interfere with proteins confer selectivity towards their targets but spectrum. Nowadays, host-targeted (HTAs) on rise, discovery development pipelines, academia pharmaceutical industry. These drugs target host involved virus life cycle considered promising alternatives to DAAs due broader lower potential resistance. Herein, we discuss an important class HTAs that modulate signal transduction pathways by targeting kinases. Kinases key enzymes control virus-host interactions. We also provide synopsis pipeline detailing kinase targets, types, therapeutic classes repurposed top developing organizations. Furthermore, detail design repurposing considerations, as well challenges, kinase-targeted antivirals, including choice binding sites, physicochemical properties, combinations.

Language: Английский

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Unraveling antiviral efficacy of multifunctional immunomodulatory triterpenoids against SARS‐COV‐2 targeting main protease and papain‐like protease

IUBMB Life, Journal Year: 2023, Volume and Issue: 76(5), P. 228 - 241

Published: Dec. 7, 2023

Abstract The coronavirus disease 2019 (COVID‐19) pandemic, caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2) may be over, but its variants continue to emerge, and patients with mild symptoms having long COVID is still under investigation. SARS‐CoV‐2 infection leading elevated cytokine levels suppressed immune responses set off storm, fatal systemic inflammation, tissue damage, multi‐organ failure. Thus, drug molecules targeting the virus‐specific proteins or capable of suppressing host inflammatory viral would provide an effective antiviral therapy against emerging concern. Evolutionarily conserved papain‐like protease (PLpro) main (Mpro) play indispensable role in virus life cycle evasion. Direct‐acting antivirals both these proteases represent attractive strategy that also expected reduce inflammation. present study has evaluated anti‐inflammatory potential natural triterpenoids: azadirachtin, withanolide_A, isoginkgetin. These inhibit Mpro PLpro proteolytic activities half‐maximal inhibitory concentrations (IC 50 ) values ranging from 1.42 32.7 μM. Isothermal titration calorimetry (ITC) analysis validated binding compounds PLpro. As expected, two compounds, withanolide_A exhibit potent anti‐SARS‐CoV‐2 activity cell‐based assays, half‐maximum concentration (EC 21.73 31.19 μM, respectively. roles azadirachtin when assessed using HEK293T cells, were found significantly CXCL10, TNFα, IL6, IL8 cytokines, which are cases COVID‐19. Interestingly, rescue decreased type‐I interferon response (IFN‐α1). results this clearly highlight triterpenoids as target SARS‐CoV‐2‐specific enzymes pathways involved virus‐mediated

Language: Английский

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Growth hormone–releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(48)

Published: Nov. 20, 2023

COVID-19 pneumonia causes acute lung injury and respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial epithelial injuries with altered diffusing capacity obstructive or restrictive physiology. Growth hormone-releasing hormone receptor (GHRH-R) is expressed in the heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses bleomycin inflammation granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced dysfunction heart a BSL-2 mouse model. Male female K18-hACE2tg mice were inoculated SARS-CoV-2/USA-WA1/2020, BSL-2-compliant recombinant VSV-eGFP-SARS-CoV-2-Spike (rVSV-SARS-CoV-2), PBS, viral load, weight loss, histopathology, gene expression compared. infected rVSV-SARS-CoV-2 treated daily subcutaneous vehicle conscious, unrestrained plethysmography performed on days 0, 3, 5 (n = 7 8). Five after infection killed, blood tissues collected for histopathology protein/gene expression. Both native SARS-CoV-2 presented similar patterns of infectivity (~60%), histopathologic changes. Daily treatment conferred recovery, reduced perivascular inflammation/pneumonia, decreased lung/heart ICAM-1 compared vehicle. rescued rate, increased expiratory parameters (Te, PEF, EEP), normalized airflow (Penh Rpef) vehicle, consistent airway inflammation. RNASeq followed protein analysis revealed heightened levels end-stage necroptosis markers, including ZBP1 pMLKL induced rVSV-SARS-CoV-2, treatment, an anti-inflammatory pro-survival mechanism action this preclinical model pneumonia.

Language: Английский

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The interference between SARS-COV-2 and Alzheimer’s disease: Potential immunological and neurobiological crosstalk from a kinase perspective reveals a delayed pandemic

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 94, P. 102195 - 102195

Published: Jan. 21, 2024

Language: Английский

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Identification of SARS-CoV-2 Main Protease Inhibitors Using Chemical Similarity Analysis Combined with Machine Learning

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(2), P. 240 - 240

Published: Feb. 12, 2024

SARS-CoV-2 Main Protease (Mpro) is an enzyme that cleaves viral polyproteins translated from the genome, which critical for replication. Mpro a target anti-SARS-CoV-2 drug development. Herein, we performed large-scale virtual screening by comparing multiple structural descriptors of reference molecules with reported anti-coronavirus activity against library >17 million compounds. Further filtering, applying two machine learning algorithms, identified eighteen computational hits as compounds high diversity and drug-like properties. The activities twelve on Mpro’s enzymatic were evaluated fluorescence resonance energy transfer (FRET) assays. Compound 13 (ZINC13878776) significantly inhibited was employed experimentally hit expansion. analogues 13a (ZINC4248385), 13b (ZNC13523222), 13c (ZINC4248365) tested inhibitors, reducing recombinant potency follows: > 13a. Then, their in plaque reduction assays using Vero CCL81 cells. Subtoxic concentrations 13a, 13c, displayed vitro antiviral IC50 mid micromolar range. Compounds 13a–c could become lead development new inhibitors improved anti-SARS-CoV-2.

Language: Английский

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Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5

Antiviral Research, Journal Year: 2023, Volume and Issue: 216, P. 105654 - 105654

Published: June 15, 2023

Language: Английский

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