Acriflavine, a clinically aproved drug, inhibits SARS-CoV-2 and other betacoronaviruses
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Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identified acriflavine as a potent papain-like protease (PL pro ) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PL pro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.
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SciScore for 10.1101/2021.03.20.436259: (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:A possible limitation for human application might be that currently used therapeutic doses, which have been proven to be safe, will not lead to high enough human systemic exposures. As there are no human pharmacokinetic data …
SciScore for 10.1101/2021.03.20.436259: (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:A possible limitation for human application might be that currently used therapeutic doses, which have been proven to be safe, will not lead to high enough human systemic exposures. As there are no human pharmacokinetic data available yet, systematic PK studies proving that exposures similar to these that have been effective in mice can also be achieved in humans and are well tolerated. Similarly, like other antiviral drugs, ACF may be administered early during the infection to enable the maximum effect. Specifically, an elderly patient population may significantly benefit from a new antiviral treatment option, as mortality in the age group 70+ is significantly increased compared to younger groups. In addition, the antiviral effect against other betacoronaviruses argues that further research into the therapeutic potential of ACF may provide protection against future zoonotic infections of betacoronaviruses. The unique mode of inhibition of ACF will also serve as a blueprint to develop new, improved drugs with a broadband activity using structure-based drug development to prepare for future coronavirus outbreaks.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT03379389 Active, not recruiting Clinical Assessment of Urinary Antiseptics Methenamine and M… Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 22. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
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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