Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein’s Receptor Binding Domain and Recombinant Human ACE2
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Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), enters the host cells through two main pathways, both involving key interactions between viral envelope-anchored spike glycoprotein of the novel coronavirus and the host receptor, angiotensin-converting enzyme 2 (ACE2). To date, SARS-CoV-2 has infected up to 26 million people worldwide; yet, there is no clinically approved drug or vaccine available. Therefore, a rapid and coordinated effort to re-purpose clinically approved drugs that prevent or disrupt these critical entry pathways of SARS-CoV-2 spike glycoprotein interaction with human ACE2, could potentially accelerate the identification and clinical advancement of prophylactic and/or treatment options against COVID-19, thus providing possible countermeasures against viral entry, pathogenesis and survival. Herein, we discovered that Ambroxol hydrochloride (AMB), and its progenitor, Bromhexine hydrochloride (BHH), both clinically approved drugs are potent effective modulators of the key interaction between the receptor binding domain (RBD) of SARS-CoV-2 spike protein and human ACE2. We also found that both compounds inhibited SARS-CoV-2 infection-induced cytopathic effect at micromolar concentrations. Therefore, in addition to the known TMPRSS2 activity of BHH; we report for the first time that the BHH and AMB pharmacophore has the capacity to target and modulate yet another key protein-protein interaction essential for the two known SARS-CoV-2 entry pathways into host cells. Altogether, the potent efficacy, excellent safety and pharmacologic profile of both drugs along with their affordability and availability, makes them promising candidates for drug repurposing as possible prophylactic and/or treatment options against SARS-CoV-2 infection.
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SciScore for 10.1101/2020.09.13.295691: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, our study has some limitations such as the use of Vero E6 cells that were selected for high expression of human ACE2 in the antiviral assay40,41. Besides, future studies exploring structural activity relationship (SAR) …
SciScore for 10.1101/2020.09.13.295691: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, our study has some limitations such as the use of Vero E6 cells that were selected for high expression of human ACE2 in the antiviral assay40,41. Besides, future studies exploring structural activity relationship (SAR) with derivatives of AMB, with a similar pharmacophore, improved efficacy and similar/better safety profile, will facilitate the discovery and pre-clinical development of new chemical molecules as potential options for COVID-19 prevention and/or treatment. SAR studies will also provide additional insight into the mode of action of this pharmacophore and aid in the rational design/discovery of new countermeasures against SARS-CoV-2 infection.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04273763 Active, not recruiting Evaluating the Efficacy and Safety of Bromhexine Hydrochlori… NCT04340349 Enrolling by invitation Low-dose Hydroxychloroquine and Bromhexine: a Novel Regimen … NCT04355026 Recruiting Use of Bromhexine and Hydroxychloroquine for Treatment of CO… NCT04424134 Recruiting BromhexIne And Spironolactone For CoronаVirUs Infection Requ… NCT04405999 Completed Prevention of Infection and Incidence of COVID-19 in Medical… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.09.13.295691: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Thereafter, the solution was discarded and the plate was washed consecutively four times with 300 µL 1X wash buffer, followed by the addition of the detection antibody (anti-ACE2 goat antibody). anti-ACE2 goat antibody).suggested: NoneExperimental Models: Cell Lines Sentences Resources The plates were passed into the BSL-3 facility where a … SciScore for 10.1101/2020.09.13.295691: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Thereafter, the solution was discarded and the plate was washed consecutively four times with 300 µL 1X wash buffer, followed by the addition of the detection antibody (anti-ACE2 goat antibody). anti-ACE2 goat antibody).suggested: NoneExperimental Models: Cell Lines Sentences Resources The plates were passed into the BSL-3 facility where a 25µL aliquot of virus inoculated cells (4000 Vero E6 cells/well) was added to each well in columns 3-22. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources The background hydrolysis was subtracted and the data was fitted to a special bell-shaped dose-response curve equation using GraphPad prism software 8.4.3. 44–47 . GraphPad prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
However, our study has some limitations such as the use of Vero E6 cells that were selected for high expression of human ACE2 in the antiviral assay40,41. Besides, future studies exploring structural activity relationship (SAR) with derivatives of AMB, with a similar pharmacophore, improved efficacy and similar/better safety profile, will facilitate the discovery and pre-clinical development of new chemical molecules as potential options for COVID-19 prevention and/or treatment. SAR studies will also provide additional insight into the mode of action of this pharmacophore and aid in the rational design/discovery of new countermeasures against SARS-CoV-2 infection. CONCLUSION AND SIGNIFICANCE Repurposing clinically approved drugs with novel mechanisms of action and/or multiple cellular targets could potentially disrupt viral pathogenesis, survival and/or prevent the viral entry and interaction with host receptor, ACE2. This approach to drug discovery could accelerate the clinical development of anti-COVID-19 prophylactics/treatments, thus providing countermeasures against COVID-19 and its impact on population health, healthcare systems, and the global economy55. Our novel findings of AMB and BHH as modulators of the binding of rhACE2 with SARS-CoV-2 Spike (RBD) protein provide new insights into the mode of action and additional molecular target(s) for AMB and its progenitor, BHH. Thus, validating this chemical class as promising leads for clinical development of novel SARS-CoV...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04273763 Active, not recruiting Evaluating the Efficacy and Safety of Bromhexine Hydrochlori... NCT04340349 Enrolling by invitation Low-dose Hydroxychloroquine and Bromhexine: a Novel Regimen ... NCT04355026 Recruiting Use of Bromhexine and Hydroxychloroquine for Treatment of CO... NCT04424134 Recruiting BromhexIne And Spironolactone For CoronаVirUs Infection Requ... NCT04405999 Completed Prevention of Infection and Incidence of COVID-19 in Medical... Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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