Inhibitory mechanism of Ambroxol and Bromhexine Hydrochlorides as potent blockers of molecular interaction between SARS-CoV-2 spike protein and human angiotensin-converting Enzyme-2

Idowu, Kehinde; Egbejimi, Anu; Kaur, Manvir; Onyenaka, Collins; Adebusuyi, Tolulope; Olaleye, Omonike A.

doi:10.1016/j.jmgm.2022.108201

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…NRP-1, known to bind furin-cleaved substrates, serves as a host component that significantly potentiates SARS-CoV-2 infectiousness by facilitating viral entry into cells [ 26 ]. Besides human angiotensin-converting enzyme 2 (hACE-2) in the previous study [ 27 ], we discovered that ambroxol might interact with NRP-1 on the cellular membrane to prevent SARS-CoV-2 entry. In addition, we found the EC 50 for ambroxol was 135.6 μM in 293T cells and 163.7 μM in A549 cells.…”

Section: Discussionmentioning

confidence: 99%

Polypharmacology of ambroxol in the treatment of COVID-19

et al. 2023

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The pandemic of COVID-19 by SARS-CoV-2 is still underway. Due to the growing development of severe symptoms, it is necessary to promote effective therapies. Ambroxol [2 - amino - 3,5 - dibromo - N - (trans - 4 - hydroxycyclohexyl) benzylamine] has long been used as one of the over-the-counter mucolytic agents to treat various respiratory diseases. Therefore, we focused on the mechanism of action of ambroxol in COVID-19 treatment. In vitro and in silico screening revealed that ambroxol may impede cell entry of SARS-CoV-2 by binding to neuropilin-1. Ambroxol could also interact with multiple inflammatory factors and signaling pathways, especially NF-κB, to interfere cytokines cascade activated by SARS-CoV-2 internalization. Furthermore, multi-pathways and proteins, such as the Cell cycle and matrix metalloproteinases, were identified as significant ambroxol-targeting pathways or molecules in PBMC and lung of severe COVID-19 patients by bioinformatics analysis. Collectively, these results suggested that ambroxol may serve as a promising therapeutic candidate for the treatment of severe SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

Polypharmacology of ambroxol in the treatment of COVID-19

et al. 2023

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“…The results show that bromhexine exhibits the lowest Ka value among the investigated drug molecules and thus, is most sensitively detected by the prepared sensor. Kenhinde et al [ 25 ] investigated the inhibition mechanism of bromohexine and ambroxol hydrochlorides as blockers of the interaction of SARS-CoV-2 spike protein with ACE2 molecules and showed that bromohexine exhibited better molecular interaction and binding than ambroxol hydrochlorides with reduced affinity. This is consistent with the results of the present study in which bromoxyn had the smallest Ka value and the most sensitive sensing.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Drug Molecule Interactions with a Newly Developed Nano-Gold-Modified Spike Protein Electrochemical Receptor Sensor

Liu

Wang

et al. 2022

Biosensors

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In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic, and the spike protein has been reported to be an important drug target for anti-COVID-19 treatment. As such, in this study, we successfully developed a novel electrochemical receptor biosensor by immobilizing the SARS-CoV-2 spike protein and using AuNPs-HRP as an electrochemical signal amplification system. Moreover, the time-current method was used to quantify seven antiviral drug compounds, such as arbidol and chloroquine diphosphate. The results show that the spike protein and the drugs are linearly correlated within a certain concentration range and that the detection sensitivity of the sensor is extremely high. In the low concentration range of linear response, the kinetics of receptor–ligand interactions are similar to that of an enzymatic reaction. Among the investigated drug molecules, bromhexine exhibits the smallest Ka value, and thus, is most sensitively detected by the sensor. Hydroxychloroquine exhibits the largest Ka value. Molecular docking simulations of the spike protein with six small-molecule drugs show that residues of this protein, such as Asp, Trp, Asn, and Gln, form hydrogen bonds with the -OH or -NH2 groups on the branched chains of small-molecule drugs. The electrochemical receptor biosensor can directly quantify the interaction between the spike protein and drugs such as abidor and hydroxychloroquine and perform kinetic studies with a limit of detection 3.3 × 10−20 mol/L, which provides a new research method and idea for receptor–ligand interactions and pharmacodynamic evaluation.

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“…и соавт. в сентябре 2020 г. описали возможность применения амброксола, активного метаболита бромгексидина, в качестве блокатора взаимодействия спайк-протеина вируса SARS-CoV-2 и рецетора АПФ2 и, таким образом нарушать проникновение вируса в клетку [31], что в последующем было подтверждено в исследовании in vitro [32]. Концентрации амброксола значительно превышали концентрации ЛС в плазме крови пациентов при применении его в стандартных дозах, что не позволяет перенести эти данные в клинику.…”

Section: муколитические средстваunclassified

Polypharmacy in Managment of in-Patients With Novel Coronavirus Disease (Covid-19)

Петров

Ryazanova

Privaltseva

et al. 2022

Farm. farmakol. (Pâtigorsk)

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The aim. To identify polypharmacy cases and develop the ways to optimize pharmacotherapy of patients with COVID-19 hospitalized in infectious disease facilities.Materials and methods. ATC/DDD analysis with calculation of DDDs/100 bed days and a sample analysis of 500 patients’ prescriptions were performed for presenting drug utilization statistics in the infectious disease facilities of Volgograd region, which had been reassigned to treat patients with COVID-19 in 2020 and 2021.Results. Five or more drugs were administered simultaneously in 96.8% of patients. Antibacterial drugs were in 74.3% of the analyzed prescriptions in 2020 and in 73.5% in 2021. The total consumption of antibiotics was 102.9 DDDs/100 bed-days in 2020 and 95.7 DDDs/100 bed-days in 2021. The cases of multiple administrations of biological disease modifying antirheumatic drugs and the use of cyclophosphamide have been identified. In 73.6% of prescriptions in 2020 and 85.4% of 2021, omeprazole at the dose of 40 mg per day was used (77.3 and 84.6 DDDs/100 bed-days, respectively). In 2021, there were cases of concomitant intravenous prescribing of acetylcysteine under the trade name of Fluimucil® with tableted forms of ambroxol and acetylcysteine under the name of ACC®. The cumulative consumption of hepatotoxic drugs was 269.2 DDDs/100 bed-days in 2020 and 401.5 DDDs/100 bed-days in 2021.Conclusion. Lack of drugs with proven effectiveness for treatment of COVID-19, worked-out treatment algorithms, a high mortality of patients in the hospitals led to polypragmasy, excessive prescribing of drugs in the hospitals. The prescription of antibacterial drugs, omeprazole, mucolytics, hepatotoxic drugs, immunosuppressors in infectious hospitals should be monitored by clinical pharmacologist.

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Inhibitory mechanism of Ambroxol and Bromhexine Hydrochlorides as potent blockers of molecular interaction between SARS-CoV-2 spike protein and human angiotensin-converting Enzyme-2

Cited by 10 publications

References 38 publications

Polypharmacology of ambroxol in the treatment of COVID-19

Polypharmacology of ambroxol in the treatment of COVID-19

Kinetics of Drug Molecule Interactions with a Newly Developed Nano-Gold-Modified Spike Protein Electrochemical Receptor Sensor

Polypharmacy in Managment of in-Patients With Novel Coronavirus Disease (Covid-19)

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