Aprotinin—Drug against Respiratory Diseases

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(13), С. 11173 - 11173

Опубликована: Июль 6, 2023

Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, widely used as antithrombotic and anti-inflammatory drug cardiac noncardiac surgeries for reduction of bleeding thus limiting the need blood transfusion. The ability to inhibit proteolytic activation some viruses leads its use antiviral prevention treatment acute respiratory virus infections. However, due incompetent interpretation several clinical trials followed by incredible controversy literature, usage nearly stopped decade worldwide. In 2015-2020, after re-analysis these trials' data restrictions were lifted This review discusses mechanisms action summarizes current knowledge prospective regarding diseases caused RNA-containing viruses, including influenza SARS-CoV-2 or part combination treatment.

Язык: Английский

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Whole-body visualization of SARS-CoV-2 biodistribution in vivo by immunoPET imaging in non-human primates

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 21, 2025

Abstract The COVID-19 pandemic has caused at least 780 million cases globally. While available treatments and vaccines have reduced the mortality rate, spread evolution of virus are ongoing processes. Despite extensive research, long-term impact SARS-CoV-2 infection is still poorly understood requires further investigation. Routine analysis provides limited access to tissues patients, necessitating alternative approaches investigate viral dissemination in organism. We address this issue by implementing a whole-body vivo imaging strategy longitudinally assess biodistribution SARS-CoV-2. demonstrate non-human primate model that single injection radiolabeled [ 89 Zr]COVA1-27-DFO human monoclonal antibody targeting preserved epitope spike protein allows longitudinal tracking positron emission tomography with computed (PET/CT). Convalescent animals exhibit persistent PET signal lungs, as well brain, three months following infection. This approach also detection various organs, including airways kidneys, exposed during acute phase. Overall, technology we developed offers comprehensive assessment distribution promising for non-invasive study long-COVID pathophysiology.

Язык: Английский

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Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo

Antiviral Research, Год журнала: 2025, Номер 239, С. 106186 - 106186

Опубликована: Май 14, 2025

Язык: Английский

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SARS-CoV-2 superinfection in CD14+ monocytes with latent human cytomegalovirus (HCMV) promotes inflammatory cascade

Virus Research, Год журнала: 2024, Номер 345, С. 199375 - 199375

Опубликована: Апрель 22, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of disease 2019 (COVID-19), has posed significant challenges to global health. While much attention been directed towards understanding primary mechanisms SARS-CoV-2 infection, emerging evidence suggests co-infections or superinfections with other viruses may contribute increased morbidity and mortality, particularly in severe cases COVID-19. Among that have reported patients SARS-CoV-2, seropositivity for Human cytomegalovirus (HCMV) is associated COVID-19 risk hospitalization. HCMV a ubiquitous beta-herpesvirus seroprevalence 60–90 % worldwide one leading causes mortality immunocompromised individuals. The sites latency include CD14+ monocytes CD34+ hematopoietic cells. In this study, we sought investigate infection latently infected HCMV. We demonstrate cells are susceptible permissive detect subgenomic transcripts indicative replication. To further molecular changes triggered by HCMV-latent monocytes, conducted RNA sequencing coupled bioinformatic differential gene analysis. results revealed differences cytokine-cytokine receptor interactions inflammatory pathways superinfected replication-competent compared heat-inactivated mock controls. Notably, there was upregulation pro-inflammatory response factors decrease anti-inflammatory factors. Taken together, these findings provide basis heightened response, offering potential avenues targeted therapeutic interventions among HCMV-infected secondary higher prevalence symptoms. Individuals seropositive human at an reactivation failure could be result co-infection cell culture model superinfection, previously shown increase epithelial upregulating angiotensin-converting enzyme-2 (ACE2) receptor. utilize major type harbors latent HCMV, This study first step toward mechanism facilitate severity

Язык: Английский

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Combined Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Reduces Molnupiravir-Induced Mutagenicity and Prevents Selection for Nirmatrelvir/Ritonavir Resistance Mutations

The Journal of Infectious Diseases, Год журнала: 2024, Номер 230(6), С. 1380 - 1383

Опубликована: Июль 8, 2024

Abstract We investigated the mutation profiles of severe acute respiratory syndrome coronavirus 2 in samples collected from a molnupiravir and nirmatrelvir/ritonavir combination therapy macaques. found that induced several nirmatrelvir resistance mutations at low abundance were not further selected therapy. Coadministration lowered magnitude mutagenetic effect molnupiravir.

Язык: Английский

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Combination Therapy with UV-4B and Molnupiravir Enhances SARS-CoV-2 Suppression

Viruses, Год журнала: 2023, Номер 15(5), С. 1175 - 1175

Опубликована: Май 16, 2023

The host targeting antiviral, UV-4B, and the RNA polymerase inhibitor, molnupiravir, are two orally available, broad-spectrum antivirals that have demonstrated potent activity against SARS-CoV-2 as monotherapy. In this work, we evaluated effectiveness of UV-4B EIDD-1931 (molnupiravir's main circulating metabolite) combination regimens beta, delta, omicron BA.2 variants in a human lung cell line. Infected ACE2 transfected A549 (ACE2-A549) cells were treated with both monotherapy combination. Viral supernatant was sampled on day three when viral titers peaked no-treatment control arm, levels infectious virus measured by plaque assay. drug-drug effect interaction between also defined using Greco Universal Response Surface Approach (URSA) model. Antiviral evaluations treatment plus enhanced antiviral all relative to These results accordance those obtained from model, these identified additive beta synergistic delta variant. Our findings highlight anti-SARS-CoV-2 potential regimens, present therapy promising therapeutic strategy SARS-CoV-2.

Язык: Английский

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Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication

RSC Advances, Год журнала: 2023, Номер 13(26), С. 17667 - 17677

Опубликована: Янв. 1, 2023

The papain-like protease (PLpro) plays a critical role in SARS-CoV-2 (SCoV-2) pathogenesis and is essential for viral replication allowing the virus to evade host immune response. Inhibitors of PLpro have great therapeutic potential, however, developing them has been challenging due PLpro's restricted substrate binding pocket. In this report, we screened 115 000-compound library inhibitors identified new pharmacophore, based on mercapto-pyrimidine fragment that reversible covalent inhibitor (RCI) inhibits cells. Compound 5 had an IC50 5.1 μM inhibition hit optimization yielded derivative with increased potency (IC50 0.85 μM, 6-fold higher). Activity profiling compound demonstrated it reacts cysteines. We show here represents class RCIs, which undergo addition elimination reaction cysteines their target proteins. further reversibility catalyzed by exogenous thiols dependent size incoming thiol. contrast, traditional RCIs are all upon Michael mechanism base-catalyzed. identify introduces more reactive warhead pronounced selectivity profile thiol ligand size. This could allow expansion RCI modality use towards larger group proteins important human disease.

Язык: Английский

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Attention Mechanism-Based Graph Neural Network Model for Effective Activity Prediction of SARS-CoV-2 Main Protease Inhibitors: Application to Drug Repurposing as Potential COVID-19 Therapy

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(22), С. 7011 - 7031

Опубликована: Ноя. 14, 2023

Compared to de novo drug discovery, repurposing provides a time-efficient way treat coronavirus disease 19 (COVID-19) that is caused by severe acute respiratory syndrome 2 (SARS-CoV-2). SARS-CoV-2 main protease (Mpro) has been proved be an attractive target due its pivotal involvement in viral replication and transcription. Here, we present graph neural network-based deep-learning (DL) strategy prioritize the existing drugs for their potential therapeutic effects against Mpro. Mpro inhibitors were represented as molecular graphs ready attention network (GAT) isomorphism (GIN) modeling predicting inhibitory activities. The result shows GAT model outperforms GIN other competitive models yields satisfactory predictions unseen inhibitors, confirming robustness generalization. mechanism of enables capture dominant substructures thus realize interpretability model. Finally, applied optimal conjunction with docking simulations screen Drug Repurposing Hub (DRH) database. As result, 18 hits best consensus prediction scores binding affinity values identified therapeutics COVID-19. Both extensive literature searching evaluations on adsorption, distribution, metabolism, excretion, toxicity (ADMET) illustrate premium drug-likeness pharmacokinetic properties candidates. Overall, our work not only effective GAT-based DL tool activity but also theoretical guidelines discovery COVID-19 treatment.

Язык: Английский

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Metabolomic Analysis and Antiviral Screening of a Marine Algae Library Yield Jobosic Acid (2,5-Dimethyltetradecanoic Acid) as a Selective Inhibitor of SARS-CoV-2

Journal of Natural Products, Год журнала: 2024, Номер 87(6), С. 1513 - 1520

Опубликована: Май 23, 2024

Current small-molecule-based SARS-CoV-2 treatments have limited global accessibility and pose the risk of inducing viral resistance. Therefore, a marine algae cyanobacteria extract library was screened for natural products that could inhibit two well-defined validated COVID-19 drug targets, disruption spike protein/ACE-2 interaction main protease (M

Язык: Английский

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Preclinical discovery and development of nirmatrelvir/ritonavir combinational therapy for the treatment of COVID-19 and the lessons learned from SARS-COV-2 variants

Expert Opinion on Drug Discovery, Год журнала: 2023, Номер 18(12), С. 1301 - 1311

Опубликована: Авг. 23, 2023

ABSTRACTIntroduction Nirmatrelvir/ritonavir (Paxlovid®) represent an oral antiviral therapy approved for the treatment of COVID-19. Extensive in vitro and vivo studies have reported promising activity nirmatrelvir/ritonavir against numerous emerging viruses. This combination consists nirmatrelvir, a protease reversible inhibitor coronavirus 3CLpro mainly metabolized by cytochrome P450 (CYP)3A4, ritonavir, CYP3A isoforms that enhances efficacy nirmatrelvir fixing its suboptimal pharmacokinetic properties.Areas covered review comprehensively examines through rigorous analysis studies. Moreover, it thoroughly assesses safety, tolerability, pharmacokinetics, SARS-COV-2 infection, based on main pre-authorization randomized controlled trials.Expert opinion has good tolerability profile. Its administration during early stages mild-to-moderate COVID-19 holds potential benefits, as can help prevent onset aberrant immune response could lead to pulmonary extra-pulmonary complications. However, drug – interactions be factor limiting use, at least populations some chronic therapies, along with risk infection relapse after treatment.KEYWORDS: Nirmatrelvir/ritonavirPaxlovidCOVID-19Protease InhibitorSARS-CoV-2 variants Article highlights Inhibiting viral proteases considered therapeutic strategy many diseases.Nirmatrelvir is been shown active coronaviruses including SARS-CoV SARS-CoV-2. It interacts strategically relevant SARS-CoV-2 protease.Investigations cellular models demonstrate SARS-CoV-2, effects terms reducing shedding both vitro.Nirmatrelvir currently administered which delays metabolization. Unfortunately, interaction drugs (e.g. anticoagulants) limits use high-risk patients.Nirmatrelvir/ritonavir encouraging treatment, but recurrence disease patients due advent mutations (3CLpro).Declaration InterestThe authors no affiliations or financial involvement any organization entity interest conflict subject matter materials discussed manuscript. includes employment, consultancies, honoraria, stock ownership options, expert testimony, grants patents received pending, royalties.Reviewer DisclosuresPeer reviewers this manuscript other relationships disclose.Additional informationFundingThis not funded.

Язык: Английский

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