Nafamostat Mesylate in lipid carrier for nasal SARS-CoV2 titer reduction in a hamster model
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Abstract
Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has been responsible for the largest pandemic in recent decades. After seemingly being in control due to consequent lock-downs and social distancing, the majority of countries faces currently a second wave of exponentially increasing infections, hospital referrals and deaths due to SARS-CoV-2-mediated disease (COVID-19). To date, no effective vaccination has been found, and wearing masks and social distancing are the only effective approaches to reduce further spreading.
However, unwillingness in the societies to distance again and consequently wear masks might be reasons for the second SARS-CoV-2 infection wave. User-friendly chemicals interfering at the host site with viral entry might be an approach to contain the pandemic. In addition, such an approach would work synergistic with vaccinations that miss new virus mutants.
Nafamostat (NM) has been shown in vitro to interfere with cellular virus entry by inhibition of the host transmembrane protease serine 2 (TMPRSS2), an enzyme required for SARS-CoV-2 spike protein cleavage, a prerequisite for cell entry.
We hypothesized that nasal application of NM in a liposomal layer (as additional mechanical barrier) could lower the nasal viral load and subsequently reduce the severity of COVID-19. We found, indeed, that nasal viral load one day post single NM application, was lowered in a hamster SARS-CoV-2 infection model. However, severity of subsequent local tissue destruction and weight loss due to pneumonitis was not favorably altered.
In conclusion, a single NM application reduced nasal viral load, but did not favorably improve the outcome of COVID-19, likely due to the short half-time of NM. Improvement of NM stability or repetitive application (which was not permitted in this animal model according to Dutch law) might circumvent these challenges.
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SciScore for 10.1101/2020.11.09.372375: (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 All slides were evaluated in a blinded fashion by a certified veterinary pathologist. Power Analysis not detected. Sex as a biological variable Animals: Hamsters have been previously described as model animals for COVID-19 (15). 8-9 weeks old female Syrian hamsters were purchased from Janvier Labs, France and included in the experiment after one week of acclimatization in the enhanced biosafety level 3 (BSL3) facility. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources A goat anti-rabbit HRP polymer (Envision +) was used as secondary antibody and color was developed with DAB + (DAKO / … SciScore for 10.1101/2020.11.09.372375: (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 All slides were evaluated in a blinded fashion by a certified veterinary pathologist. Power Analysis not detected. Sex as a biological variable Animals: Hamsters have been previously described as model animals for COVID-19 (15). 8-9 weeks old female Syrian hamsters were purchased from Janvier Labs, France and included in the experiment after one week of acclimatization in the enhanced biosafety level 3 (BSL3) facility. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources A goat anti-rabbit HRP polymer (Envision +) was used as secondary antibody and color was developed with DAB + (DAKO / Agilent Technologies, Santa Clara, USA). anti-rabbitsuggested: NoneExperimental Models: Cell Lines Sentences Resources Virus: SARS-CoV-2 isolates (Human/NL/Lelystad/2020) were propagated in Vero E6 cells (ATCC) in Eagle’s minimal essential medium (Gibco) supplemented with 1% L-glutamine, 1% nonessential amino acids and 1% antibiotics, and 5% fetal bovine serum at 37 °C. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Software used for calculation was GraphPad Prism version 8. 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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
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.
- No funding statement was detected.
- No protocol registration statement was detected.
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