Nafamostat mesylate initially reduces SARS-CoV-2 viral load in hamsters, according to study

The researchers found that nafamostat mesylate, when injected into the nasal cavity of Syrian hamsters, can reduce the initial viral load of SARS-CoV-2 in the nose. However, this effect was temporary and further tests are needed to determine clinically significant effects. The hunt group results are available on the prepress server bioRxiv*.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the pathogen responsible for the ongoing coronavirus pandemic 2019 (COVID-19) – affects the respiratory tract in humans. It is commonly transmitted by close contact with infected people via airborne particles and aerosols.

The virus’s spike protein (protein S) infects human host cells by binding to angiotensin converting enzyme 2 (ACE2). In situ RNA mapping revealed that ACE2 expression is highest in the nose, decreasing as it travels down the upper respiratory tract. Similarly, SARS-CoV-2 infection is greater in upper lung epithelial cultures than in lower regions. Therefore, the first symptoms of infection are often a runny nose, congestion and sore throat.

Although various strategies such as social distancing, wearing masks, quarantines and intensive testing have been implemented almost around the world, these have had limited success in many places. Other strategies, such as vaccines and therapies, are still in development. These will take time to develop and distribute.

Meanwhile, a possible strategy could be to block the virus from entering the upper respiratory tract. This could also be used in conjunction with vaccination or other antiviral therapies.

Nafamostat Mesylate (NM) is an anticoagulant approved for use in Japan. It has also been shown to be a potent inhibitor of spike protein-mediated membrane fusion and an inhibitor of SARS-CoV-2 entry into human lung epithelial cells. in vitro.

Test on hamsters with intranasal application of nafamostat mesylate

In a new study on Syrian hamsters, researchers based in Germany and the Netherlands tested the effectiveness of NM in reducing nasal viral load and COVID-19 severity. The researchers also tested to see if adding NM to a liposome layer could increase the stability of NM in the nose and act as a mechanical barrier to virus infection.

The authors applied NM intranasally to female Syrian hamsters and, after 5 minutes, inoculated them with SARS-CoV-2, also applied through the nose. They analyzed viral loads in animals from nasal exchanges, which were collected 1 and 3 days after infection.

Loss of body weight is not prevented by nasal application of a single Nafamostat mesylate +/- lipid carrier. Every 10 animals (8 animals from day 2 onwards) were pretreated by single application of nasal treatment as indicated and weighed daily inoculation after nasal inoculation of SARS-CoV2 virus. All animals were euthanized by day 7 pi or when they reached the clinical endpoint (weight loss> 20% compared to day 0). The error bars represent the standard deviation. NM Nafamostat mesylate.

They found significantly reduced viral loads in NM-treated animals in lipids when tested one day after infection. But there was no difference in viral loads after 3 days. All animals lost weight after infection, weight loss being an indication of the severity of the disease.

Immunochemical tests also showed that the nasal epithelium in all animals, regardless of the type of treatment received, was strongly positive for the virus nucleoproteins. Examination of the tissues of the nasal cavities showed inflammation and presence of mucus and in the nose. In addition, the nasal epithelial tissues were destroyed or severely damaged.

Temporary reduction in viral load

Although there was a large decrease in viral load in the nose, this effect was temporary and did not affect the onset or severity of the disease. The addition of the lipid carrier also did not affect the viral load much.

Although NM has effectively prevented the entry of SARS-CoV-2 previously in vitro experiments, NM has an intravenous half-life of only eight minutes. Therefore, a single application may not be sufficient to achieve sufficient protection. It is also likely that the hamster experiment did not simulate early infection, but rather the later stages of infection, with the virus moving directly to the lungs from the nose and throat.

However, another experiment on ferrets with nasal lipopeptide application showed positive results, where the dose and route of application were different. Therefore, a different experimental design, together with the addition of lipopeptide with NM, may be an effective approach to reduce viral load and disease severity.

Therefore, the research group’s experiments show that applying NM to hamsters, with or without lipid carriers, can change the nasal viral load, which can reduce the risk of transmission and the severity of the disease. In terms of its potential in COVID-19 therapy, NM is something that could perhaps be applied as an inhaler or nasal spray. However, clinical success will depend on further testing and optimization of local stability.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or treated as consolidated information.