Learning from Protein Engineering by Deconvolution of Multi‐Mutational Variants

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(36)

Published: June 17, 2024

Abstract This review analyzes a development in biochemistry, enzymology and biotechnology that originally came as surprise. Following the establishment of directed evolution stereoselective enzymes organic chemistry, concept partial or complete deconvolution selective multi‐mutational variants was introduced. Early experiments led to finding mutations can interact cooperatively antagonistically with one another, not just additively. During past decade, this phenomenon shown be general. In some studies, molecular dynamics (MD) quantum mechanics/molecular mechanics (QM/MM) computations were performed order shed light on origin non‐additivity at all stages an evolutionary upward climb. Data used construct unique multi‐dimensional rugged fitness pathway landscapes, which provide mechanistic insights different from traditional landscapes. Along related line, biochemists have long tested result introducing two point enzyme for reasons, followed by comparison respective double mutant so‐called cycles, showed only additive effects, but more recently also uncovered cooperative antagonistic non‐additive effects. We conclude suggestions future work, call unified overall picture epistasis.

Language: Английский

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Inhibitory Efficacy of Main Components of Scutellaria baicalensis on the Interaction between Spike Protein of SARS-CoV-2 and Human Angiotensin-Converting Enzyme II

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2935 - 2935

Published: March 2, 2024

Blocking the interaction between SARS-CoV-2 spike protein and human angiotensin-converting enzyme II (hACE2) serves as a therapeutic strategy for treating COVID-19. Traditional Chinese medicine (TCM) treatments containing bioactive products could alleviate symptoms of severe However, emergence variants has complicated process developing broad-spectrum drugs. As such, aim this study was to explore efficacy TCM against through targeting viral with hACE2 receptor. Antiviral activity systematically evaluated using pseudovirus system. Scutellaria baicalensis (S. baicalensis) found be effective infection, it mediated protein. Moreover, active molecules S. were identified analyzed. Baicalein baicalin, flavone glycoside in baicalensis, respectively, exhibited strong inhibitory activities protein, respectively. Under optimized conditions, virus infection inhibited by 98% via baicalein-treated baicalin-treated hACE2. In summary, we potential inhibitors from that mediate Omicron Future studies on application baicalein baicalin are needed.

Language: Английский

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Targeting furin, a cellular proprotein convertase, for COVID-19 prevention and therapeutics

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(7), P. 104026 - 104026

Published: May 17, 2024

Language: Английский

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Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 19, 2024

The coronavirus disease 2019 (COVID-19) pandemic triggered an unprecedented concentration of economic and research efforts to generate knowledge at unequalled speed on deregulated interferon type I signalling nuclear factor kappa light chain enhancer in B-cells (NF-κB)-driven interleukin (IL)-1β, IL-6, IL-18 secretion causing cytokine storms. translation the how resulting systemic inflammation can lead life-threatening complications into novel treatments vaccine technologies is underway. Nevertheless, previously existing role cytoplasmatic or circulating self-DNA as a pro-inflammatory damage-associated molecular pattern (DAMP) was largely ignored. Pathologies reported ‘ de novo ’ for patients infected with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 be outcomes self-DNA-driven fact had been linked earlier different contexts, e.g., infection Human Immunodeficiency Virus (HIV)-1, sterile inflammation, autoimmune diseases. highlight particularly synergies other DAMPs render immunogenic properties normally non-immunogenic extracellular self-DNA, discuss shared features gp41 unit HIV-1 envelope protein SARS-CoV 2 Spike that enable SARS-CoV-2 interact cell membranes, trigger syncytia formation, inflict damage their host’s DNA, – likely own benefit. These similarities motivate speculations similar mechanisms those driven by explain inflammatory contributes some most frequent adverse events after vaccination BNT162b2 mRNA (Pfizer/BioNTech) mRNA-1273 (Moderna) vaccine, i.e., myocarditis, herpes zoster, rheumatoid arthritis, nephritis hepatitis, new-onset lupus erythematosus, flare-ups psoriasis lupus. hope wider application lessons learned from experiences COVID-19 new vaccines combat future non-COVID-19

Language: Английский

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Silver Nanoparticle‐Mediated Antiviral Efficacy against Enveloped Viruses: A Comprehensive Review

Global Challenges, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Abstract Viral infections continue to pose a significant challenge global health, with increasing resistance conventional antiviral therapies highlighting the urgent need for alternative treatment strategies. Silver nanoparticles (AgNPs) have attracted attention as broad‐spectrum agents due their unique physicochemical properties and ability target multiple stages of viral infection. This review provides comprehensive analysis mechanisms AgNPs, efficacy against clinically relevant enveloped viruses such influenza, herpes simplex, hepatitis B, coronaviruses. How key nanoparticle characteristics, including size, shape, surface functionalization, synthesis methods, influence performance is examined. Studies indicate that AgNPs exert effects through direct interactions particles, inhibition adhesion, entry into host cells disruption replication. Furthermore, potential applications in therapeutic formulations, coatings, nanomedicine‐based strategies are explored. Despite promise, challenges regarding cytotoxicity, stability, large‐scale production must be addressed ensure safe effective clinical use. highlights transformative therapy further investigation facilitate translation fight emerging drug‐resistant infections.

Language: Английский

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Capture of fusion-intermediate conformations of SARS-CoV-2 spike requires receptor binding and cleavage at either the S1/S2 or S2’ site

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(4), P. e1012808 - e1012808

Published: April 8, 2025

Although structures of pre- and post-fusion conformations SARS-CoV-2 spikes have been solved by cryo-electron microscopy, the transient spike that mediate virus fusion with host cell membranes remain poorly understood. In this study, we used a peptide inhibitor corresponding to heptad repeat 2 (HR2) in S2 transmembrane subunit investigate fusion-intermediate involve exposure highly conserved 1 (HR1). The HR2 disrupts assembly HR1 regions spike, which form six-helix bundle during transition conformation. We show binding S1 ACE2 is sufficient induce conformational changes allow shedding enable bind inhibit membrane fusion. When TMPRSS2 also present, captures an S2’ intermediate though proportion relative lower Omicron variants than pre-Omicron variants. lacking natural S1/S2 furin cleavage site, alone not for trapping intermediates, but presence allows intermediate. These results indicate that, addition engagement, at least one needed unwinding into peptide-sensitive, Our findings elucidate expose sites on could be targeted inhibitors or antibodies.

Language: Английский

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Exploring TMPRSS2 Drug Target to Combat Influenza and Coronavirus Infection

Scientifica, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Respiratory viral infections, including influenza and coronaviruses, present significant health risks worldwide. The recent COVID‐19 pandemic highlights the urgent need for novel effective antiviral agents. host cell protease, transmembrane serine protease 2 (TMPRSS2), facilitates pathogenesis by playing a critical role in invasion disease progression. This is coexpressed with receptors of angiotensin‐converting enzyme (ACE2) SARS‐CoV‐2 human respiratory tract plays activating proteins spreading. TMPRSS2 activates coronavirus spike (S) protein permits membrane fusion entry cleaving virus surface glycoproteins. It also hemagglutinin (HA) protein, an necessary spread virus. inhibitors can reduce propagation morbidity blocking into cells reducing spread, inflammation, severity. review examines replication pathogenicity. offers potential avenues to develop targeted antivirals inhibit function, suggesting possible focus on development. Ultimately, seeks contribute improving public outcomes related these infections.

Language: Английский

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A human monoclonal antibody neutralizes SARS-CoV-2 Omicron variants by targeting the upstream region of spike protein HR2 motif

hLife, Journal Year: 2024, Volume and Issue: 2(3), P. 126 - 140

Published: Feb. 9, 2024

The continuous emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants means there is a need to explore additional strategies develop broad-spectrum vaccines or therapeutics for individuals remaining at risk disease 2019 (COVID-19). Neutralizing monoclonal antibody (mAb) that binds the conserved S2 subunit SARS-CoV-2 spike (S) protein alone, in combination with mAb receptor-binding domain (RBD) S protein, might be effective eliciting protection from infection by variety variants. Using high-throughput single-cell immunoglobulin sequencing B cells COVID-19-convalescent donors, we identified high-affinity S2-specific mAb-39, could inhibit original strain, Omicron BA.1, BA.2.86, BA.4, BA.5, and EG.5.1 protein-mediated membrane fusion, leading neutralization these pseudoviral infections. Moreover, mAb-39 also improve neutralizing activity anti-RBD against highly neutralization-resistant Molecular docking point mutation analyses revealed recognized epitopes within upstream region heptad repeat (HR2) motif subunit. Collectively, findings demonstrate targeting HR2 (e.g., using mAbs) provides novel strategy preventing its

Language: Английский

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Safety and Efficacy of Camostat Mesylate for Covid-19: a systematic review and Meta-analysis of Randomized controlled trials

BMC Infectious Diseases, Journal Year: 2024, Volume and Issue: 24(1)

Published: July 19, 2024

Abstract Background Camostat mesylate, an oral serine protease inhibitor, is a powerful TMPRSS2 inhibitor and has been reported as possible antiviral treatment against COVID-19. Therefore, we aim to assess the safety efficacy of camostat mesylate for COVID-19 treatment. Methods A systematic review meta-analysis synthesizing randomized controlled trials from PubMed, Scopus, Embase, Cochrane, Web Science, clinical trials.gov, medrxiv until June 2023. The outcomes were pooled using Mean difference (MD) continuous risk ratio (RR) dichotomous outcomes. protocol registered in PROSPERO with ID CRD42023439633. Results Nine RCTs, including 1,623 patients, included this analysis. There was no between placebo producing negative PCR test results at 1–7 days (RR: 0.76, 95% CI: [0.54, 1.06] P = 0.1), 8–14 1.02, [0.84, 1.23] 0.87), or 15–21 0.99, [0.82, 1.19] 0.90); resolution symptoms 0.94 (95% 0.58, 1.53) 0.81), 0.91, [0.74, 1.11] 0.33, ), 0.77, [0.40, 1.51] 0.45); time symptom improvement (MD:-0.38 weeks [-1.42, 0.66] 0.47, I 2 85%). Conclusion did not improve patients COVID-19, compared placebo.

Language: Английский

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Engineering a NanoBiT biosensor for detecting angiotensin-converting enzyme-2 (hACE2) interaction with SARS-CoV-2 spike protein and screening the inhibitors to block hACE2 and spike interaction

Biosensors and Bioelectronics, Journal Year: 2024, Volume and Issue: 263, P. 116630 - 116630

Published: Aug. 3, 2024

Language: Английский

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