An increase in the half-life of remdesivir for COVID-19 treatment

The rapid outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the coronavirus disease 2019 (COVID-19) pandemic and, to date, it has claimed more than 5.16 million lives worldwide.

Study: Nanoviricide’s platform technology based NV-CoV-2 polymer increases the half-life of Remdesivir in vivo. Image Credit: ker_vii/ Shutterstock

Scientists have characterized the virus and reported that this virus contains a positive-sense RNA genome that encodes accessory and structural proteins. The main function of the spike protein of the SARS-CoV-2 virus is invading the host cell.

As per the mechanism, the receptor-binding domain (RBD) of the S1 domain of the spike protein binds with the ACE2 receptor of the host. The S2 domain promotes fusion of the membranes and, thereby, the virus infects the host cell. The virus uses hosts’ machinery to replicate using the virus’s RNA-dependent RNA polymerase (RdRp).

Viral diseases and remdesivir

The non-structural proteins are unique among different strains of coronaviruses and are used as an important drug target. For instance, sofosbuvir (a synthetic analog 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 coronaviruses. This is because of its ability to restrict viral replication by inhibiting RNA polymerases (RdRp4).

In vitro studies have revealed that RDV is effective against Middle East 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 for the treatment of COVID-19 infection. Interestingly, an animal model using rhesus monkeys showed that RDV treatment effectively prevented MERS-CoV and Ebola virus.

Additionally, this drug was also effective in protecting African green monkeys from the Nipah virus. Also, a randomized study using SARS-CoV-2 infected rhesus monkeys showed that RDV treatment improved respiratory symptoms and lung damage within 12 hours of treatment.

Limitations of remdesivir in human clinical studies

However, in terms of the efficacy of RDV, the outcomes of the in vitro animal studies do not match with the clinical outcomes using humans.

Additionally, previous studies have revealed that humans showed some negative side effects. For instance, when a patient infected with Ebola was treated with RDV, an increase in the enzyme that causes severe liver damage was observed.

Similarly, a study that included three patients infected with SARS-CoV-2 and subjected 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 efficacy of remdesivir limited to animal studies and how can this be rectified?

Scientists have revealed that the efficacy of RDV has been limited to in vivo studies because of its low stability in the plasma.

To enhance RDV efficacy, a previous study encapsulated RDV encapsulated in lab-made nano-polymer NV-CoV-2-R and reported that the polymer protected RDV from plasma-mediated catabolism. This is because the polymer protected the drug from degrading in the bloodstream.

Recently, the same group of scientists has extended the above-mentioned research by conducting experiments using in vivo rat models of systemic exposure of NV-CoV-2 (Polymer) and NV-CoV-2-R (Polymer encapsulated Remdesivir) once per day for five days (0, 1, 3, 5, and 7), over a seven-day time period.

This study is available on the bioRxiv* preprint server.

The study

In this study, scientists used MS-HPLC chromatography to investigate the plasma samples obtained from the control and treated rat subjects. MS-HPLC analysis revealed that in the NV-CoV-2-R sample, an RDV peak was observed, 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.

Scientists explained that the nanoviricide biomimetic polymer attaches and engulfs a virus particle into the polymeric nanoviricide, similar to a “Venus-flytrap.” After the viral particles are engulfed, it gets destroyed. The virus binding ligand region can be altered using a plug-and-play approach, which enables this nano-medicine 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 coronaviruses. NV-CoV-2 itself has antiviral properties and RDV when encapsulated is protected from plasma-mediated degradation in the bloodstream.

Conclusion

In this study, researchers analyzed several drug candidates to investigate their efficacy against a broad spectrum of coronaviruses in cell culture studies. Among the tested drug candidates, NV-CoV-2-R revealed 15-times more effectiveness than favipiravir against two different coronaviruses, namely, h-CoV-NL63 and HCoV-229E.

This study showed that to enhance the efficacy of RDV in humans, it is important to encapsulate the drug to protect it from getting degraded in the bloodstream.

*Important notice

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

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.