The rapid outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the pandemic with coronavirus disease 2019 (COVID-19), and to date it has claimed more than 5.16 million lives worldwide.
Study: Nanoviricide platform technology-based NV-CoV-2 polymer increases Remdesivir half-life in vivo. Image credit: ker_vii / Shutterstock
Researchers have characterized the virus and reported that this virus contains a positive-sense RNA genome that encodes auxiliary proteins and structural proteins. The main function of the tip protein from the SARS-CoV-2 virus is to invade the host cell.
According to the mechanism, the receptor binding domain (RBD) of the S1 domain of the nail protein binds to the host’s ACE2 receptor. The S2 domain promotes fusion of the membranes, thereby infecting the virus with the host cell. The virus uses host machinery to replicate using the virus’ RNA-dependent RNA polymerase (RdRp).
Viral diseases and remdesivir
The non-structural proteins are unique among different strains of coronavirus and are used as an important drug target. For example, sofosbuvir (a synthetic analogue of nucleosides and nucleotides) has been used to treat hepatitis C infection as it blocks RdRp.
Another nucleotide analog, namely remdesivir (RDV), formerly known as GS-5734, has been effective against coronavirus. This is due to its ability to limit viral replication by inhibiting RNA polymerases (RdRp4).
In vitro studies have revealed that RDV is effective against Middle Eastern respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2.
Based on the various clinical trials and previous studies, the US Food and Drug Administration (FDA) approved the use of RDV to treat COVID-19 infection. Interestingly, an animal model using rhesus monkeys showed that RDV treatment effectively prevented MERS-CoV and Ebola virus.
In addition, this drug was also effective in protecting African green monkeys from the Nipah virus. A randomized study with SARS-CoV-2-infected rhesus monkeys also showed that RDV treatment improved respiratory symptoms and lung damage within 12 hours of treatment.
Limitations of remdesivir in human clinical trials
But in terms of the effectiveness of RDV, the results of in vitro animal experiments are not consistent with human clinical results.
In addition, previous studies have revealed that humans showed some negative side effects. For example, when a patient infected with Ebola was treated with RDV, an increase in the enzyme causing severe liver damage was observed.
Similarly, a study involving three patients infected with SARS-CoV-2 and exposed to RDV treatment showed an increase in an enzyme that could damage the liver. Some other side effects include kidney damage, nausea and vomiting.
Why is the effect of remdesivir limited to animal experiments and how can this be corrected?
Researchers have revealed that the effect of RDV has been limited to in vivo studies due to its low plasma stability.
To increase RDV efficiency, a previous study encapsulated RDV encapsulated in laboratory-produced nanopolymer NV-CoV-2-R and reported that the polymer protected RDV from plasma-mediated catabolism. This is because the polymer protected the drug from degradation in the bloodstream.
Recently, the same group of scientists has expanded the above research by conducting experiments using. in vivo rat models of systemic exposure to NV-CoV-2 (polymer) and NV-CoV-2-R (polymer-encapsulated Remdesivir) once daily for five days (0, 1, 3, 5 and 7), over a seven-day period.
This study is available at bioRxiv* preprint server.
In this study, scientists used MS-HPLC chromatography to examine plasma samples obtained from control and treated rat subjects. MS-HPLC analysis revealed that an RDV peak was observed in the NV-CoV-2-R sample, but this was not the case in the sample containing only NV-CoV2. The body weight measurements of the uninfected rats after administration of the test drug candidates, i.e. NV-CoV-2 and NV-CoV-2-R, revealed no toxic effect.
Researchers explained that the nanoviricidal biomimetic polymer attaches and engulfs a virus particle in the polymeric nanoviricide, similar to a “Venus trap”. After the virus particles are swallowed, they are destroyed. The virus-binding ligand region can be altered using a plug-and-play approach, which allows this nanomedicine to attack different types of viruses.
The authors of this study revealed that the newly developed NV-CoV-2-R drug has a dual effect on coronavirus. NV-CoV-2 itself has antiviral properties, and RDV, when encapsulated, is protected against plasma-mediated degradation in the bloodstream.
In this study, researchers analyzed several drug candidates to test their efficacy against a broad spectrum of coronavirus in cell culture studies. Among the drug candidates tested, NV-CoV-2-R revealed 15 times more efficacy than favipiravir against two different coronaviruses, namely h-CoV-NL63 and HCoV-229E.
This study showed that in order to increase the effectiveness of RDV in humans, it is important to encapsulate the drug to protect it from being broken down in the bloodstream.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered as crucial, guide clinical practice / health-related behavior or be treated as established information.