Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors

ACS Omega, Journal Year: 2022, Volume and Issue: 7(32), P. 27950 - 27958

Published: Aug. 8, 2022

Finding antivirals for SARS-CoV-2 is still a major challenge, and many computational experimental approaches have been employed to find solution this problem. While the global vaccination campaigns are primary driver of controlling current pandemic, orally bioavailable small-molecule drugs biologics critical overcome issue. Improved therapeutics prophylactics required treat people with circulating emerging new variants, addressing severe infection, underlying or immunocompromised conditions. The envelope spike challenging target viral entry inhibitors. Pindolol presented good docking score in previous virtual screening using calculations after Food Drug Administration (FDA)-approved drug library 2400 molecules as potential candidates block protein interaction angiotensin-converting enzyme 2 (ACE-2). Here, we expanded evaluation identify five beta-blockers against several techniques, such microscale thermophoresis, NanoDSF, vitro assays different cell lines. These data identified carvedilol Kd 364 ± 22 nM activity (EC50 7.57 μM, CC50 18.07 μM) Calu-3 cells. We shown how can apply multiple that be further optimized improve anti-SARS-CoV-2 activity.

Language: Английский

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Synthesis and Evaluation of 9-Aminoacridines with SARS-CoV-2 Antiviral Activity

ACS Omega, Journal Year: 2023, Volume and Issue: 8(43), P. 40817 - 40822

Published: Oct. 19, 2023

There have been relatively few small molecules developed with direct activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two existing antimalarial drugs, pyronaridine and quinacrine, display whole cell SARS-CoV-2 in A549 + ACE2 cells (pretreatment, IC50 = 0.23 0.19 μM, respectively) moderate cytotoxicity (CC50 11.53 9.24 respectively). Moreover, displays vitro PLpro (IC50 1.8 μM). Given their antiviral activity, these compounds are strong candidates for repurposing COVID-19 prompt us to study structure–activity relationship of 9-aminoacridine scaffold using traditional medicinal chemistry identify promising new analogs. Our studies identified several novel analogs possessing potent U2-OS GFP 1-10 1-11 < 1.0 μM) as well > 4.0 Compounds such 7g, 9c, 7e were more active, demonstrating selectivity indices SI 10, 9c displayed strongest ≤ 0.42 CC50 ≥ 4.41 10) among them, indicating that it has potential a lead molecule this series COVID-19.

Language: Английский

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Application of Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung and Trachea Exposure of Pyronaridine and Artesunate in Hamsters

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(3), P. 838 - 838

Published: March 3, 2023

A fixed-dose combination of pyronaridine and artesunate, one the artemisinin-based therapies, has been used as a potent antimalarial treatment regimen. Recently, several studies have reported antiviral effects both drugs against severe acute respiratory syndrome coronavirus two (SARS-CoV-2). However, there are limited data on pharmacokinetics (PKs), lung, trachea exposures that could be correlated with artesunate. The purpose this study was to evaluate pharmacokinetics, distribution pyronaridine, dihydroartemisinin (an active metabolite artesunate) using minimal physiologically-based pharmacokinetic (PBPK) model. major target tissues for evaluating dose metrics blood, trachea, nontarget were lumped together into rest body. predictive performance PBPK model evaluated visual inspection between observations predictions, (average) fold error, sensitivity analysis. developed models applied multiple-dosing simulation daily oral steady state reached about three four days after first dosing an accumulation ratio calculated 1.8. artesunate not since compounds achieved by multiple dosing. elimination half-life estimated 19.8 0.4 h, respectively. Pyronaridine extensively distributed lung lung-to-blood trachea-to-blood concentration ratios (=Cavg,tissue/Cavg,blood) 25.83 12.41 at state, Also, AUC (dihydroartemisinin) 3.34 (1.51) 0.34 (0.15). results provide scientific basis interpreting dose–exposure–response relationship COVID-19 drug repurposing.

Language: Английский

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Arylamines QSAR-Based Design and Molecular Dynamics of New Phenylthiophene and Benzimidazole Derivatives with Affinity for the C111, Y268, and H73 Sites of SARS-CoV-2 PLpro Enzyme

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 606 - 606

Published: May 9, 2024

A non-structural SARS-CoV-2 protein, PLpro, is involved in post-translational modifications cells, allowing the evasion of antiviral immune response mechanisms. In this study, potential PLpro inhibitory drugs were designed using QSAR, molecular docking, and dynamics. combined QSAR equation with physicochemical Free-Wilson descriptors was formulated. The r2, q2, r2test values 0.833, 0.770, 0.721, respectively. From equation, it found that presence an aromatic ring a basic nitrogen atom crucial for obtaining good activity. Then, series structures binding sites C111, Y268, H73 created. best compounds to exhibit pIC50 9.124 docking scoring -14 kcal/mol. stability cavities confirmed by dynamics studies. high number stable contacts interactions over time exhibited aryl-thiophenes Pred14 Pred15, making them candidates.

Language: Английский

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Multiple approaches to repurposing drugs for neuroblastoma

Bioorganic & Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 73, P. 117043 - 117043

Published: Oct. 4, 2022

Language: Английский

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Learning from COVID-19: How drug hunters can prepare for the next pandemic

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(10), P. 103723 - 103723

Published: July 22, 2023

Language: Английский

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Transporter Inhibition Profile for the Antivirals Tilorone, Quinacrine and Pyronaridine

ACS Omega, Journal Year: 2023, Volume and Issue: 8(13), P. 12532 - 12537

Published: March 24, 2023

Pyronaridine, tilorone and quinacrine are cationic molecules that have in vitro activity against Ebola, SARS-CoV-2 other viruses. All three also demonstrated vivo Ebola mice, while pyronaridine showed efficacy mice. We recently tested these antivirals human organic cation transporters (OCTs) apical multidrug toxin extruders (MATEs). Quinacrine was found to be an inhibitor of OCT2, were less potent, displayed variability depending on the substrate used. To assess whether any potential interactions with additional transporters, we now screened them at 10 μM various efflux uptake including P-gp, OATP1B3, OAT1, OAT3, MRP1, MRP2, MRP3, BCRP, as well confirmational testing OCT1, MATE1 MATE2K. Interestingly, this study appears a more potent OCT1 OCT2 than or quinacrine. However, both appear inhibitors None compounds inhibited P-gp OATP1B3. Similarly, previously do not inhibit OATP1B1 confirmed behaves similarly. In total, observations suggest only interact OCTs MATEs differing extents, suggesting they may involved fewer clinically relevant drug-transporter involving pharmaceutical substrates major tested.

Language: Английский

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Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses

mBio, Journal Year: 2023, Volume and Issue: 14(5)

Published: Aug. 15, 2023

ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to be one of the largest dangers human health around world. need for effective antiviral and anti-inflammatory treatments is still extremely high as newly emerging variants threaten efficacy currently used treatment options. Many compounds are at inhibiting SARS-CoV-2 infection in vitro but fail recapitulate that vivo . There a major demand drugs efficacious broadly highly pathogenic coronaviruses including SARS-CoV-2, its close relatives SARS-CoV-1 Middle East (MERS-CoV). One drug with potential join small subset active both orally bioavailable pyronaridine triphosphate, which has now been published show A549 cells K18-hACE2 mouse model, respectively, functioning protease inhibitor papain-like (PLpro). In our studies, resulted significant improvements lung inflammatory pathology, reducing pro-inflammatory cytokine chemokine levels, weight loss seen model associated severity three models, SARS-CoV-1, MERS-CoV. Additionally, we found can safely effectively combined therapeutics molnupiravir nirmatrelvir (main component Paxlovid) there was evidence synergistic effect further reduced viral titers, levels. These results indicate represents an excellent therapeutic candidate COVID-19 individually, or combination other approved antivirals well option such MERS-CoV, future yet emerge. IMPORTANCE Pyronaridine tetraphosphate on WHO Essential Medicine List importance widely available safe malaria. We find across models using multiple viruses responsible previous outbreaks. additively combines current (protease inhibit infections. many demonstrate cellular few this level impact represent promising pandemic outbreaks well.

Language: Английский

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Oral Pyronaridine Tetraphosphate Reduces Tissue Presence of Parasites in a Mouse Model of Chagas Disease

ACS Omega, Journal Year: 2024, Volume and Issue: 9(35), P. 37288 - 37298

Published: Aug. 20, 2024

The eukaryotic parasite

Language: Английский

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High-Throughput Empirical and Virtual Screening to Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 24, 2024

Abstract Therapy resistance in breast cancer is increasingly attributed to polyploid giant cells (PGCCs), which arise through whole-genome doubling and exhibit heightened resilience standard treatments. Characterized by enlarged nuclei increased DNA content, these tend be dormant under therapeutic stress, driving disease relapse. Despite their critical role resistance, strategies effectively target PGCCs are limited, largely due the lack of high-throughput methods for assessing viability. Traditional assays sensitivity needed detect PGCC-specific elimination, prompting development novel approaches. To address this challenge, we developed a single-cell morphological analysis workflow designed differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using method, screened library 2,726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, macrocyclic lactones. Notably, RNA-Seq treated with lactone Pyronaridine revealed AXL inhibition as potential strategy targeting PGCCs. Although our pipeline powerful, empirically testing all existing impractical inefficient. overcome limitation, trained machine learning model predict efficacy silico , integrating chemical fingerprints compound descriptions from prior publications databases. The demonstrated high correlation experimental outcomes predicted efficacious an expanded over 6,000 drugs. Among top-ranked predictions, experimentally validated two potent PGCC inhibitors. These findings underscore synergistic empirical screening learning-based virtual accelerate discovery therapies, particularly therapy-resistant cancer.

Language: Английский

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