the oral nucleoside analog of Remdesivir improved the pathogenesis of SARS-CoV-2 in mice


The 2019 coronavirus disease (COVID-19) pandemic has infected an estimated 225 million people and killed more than 4.64 million worldwide. This pandemic is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which was first reported in Wuhan, China in 2019.

Study: Therapeutic efficacy of an oral nucleoside analog of remdesivir against the pathogenesis of SARS-CoV-2 in mice. Image Credit: Hamara / Shutterstock

Importance of therapeutics to contain the COVID-19 pandemic

Several vaccines have received Emergency Use Authorization (EUA) from various global regulatory agencies, and in many countries vaccination programs have started. Although the initial vaccination rate was extremely high in the United States, recent reports have indicated that vaccination rates have declined due to reluctance to vaccinate. In many other countries, sufficient vaccines are not available for the entire population and, as a result, the vaccination process has been slow. These events are fueling the outbreak of SARS-CoV-2 variants, many of which are more virulent than the original strain and may elude vaccine-induced immune responses and acquired immunity following natural infection with COVID-19. Therefore, oral antivirals are needed to treat cases of COVID-19 in unvaccinated and immunocompromised people. These antivirals could also be effective in the treatment of cases of vaccine rupture.

Scientists believe that if next-generation oral coronavirus (CoV) antivirals could be used during the early stages of infection, it could reduce household transmissions, minimize the long-term sequelae of COVID-19, and lower the rate. hospitalization.

Therapies for COVID-19 disease

Several direct-acting antiviral (DAA) therapies are used for the treatment of COVID-19 patients, for example, EUA-approved monoclonal antibodies (mAbs) and FDA-approved remdesivir (RDV, GS-5734). Since all mAbs must be given by injection, they cannot easily be used to treat patients. In addition, some of the worrying variants of SARS-CoV-2 (VoC) are resistant to the first line of mAb therapies. Many AADs such as the nucleoside analogs molnupiravir (MPV, EIDD-2801), AT-527 and the MPro inhibitor PF-07321332 are the subject of clinical trials in humans.

Benefits of nucleoside analog drugs

The SARS-CoV-2 spike protein can be mutated and most therapies and vaccines that have been developed target this protein. Unlike mAbs, which also target the spike protein of SARS-CoV-2, nucleoside analog drugs target highly conserved regions such as the viral enzyme conserved among CoV i.e. RNA polymerase RNA -dependent (RdRp) nsp12. Therefore, the high degree of conserved regions makes these drugs effective against many variants.

Although previous research has described RDV’s therapeutic efficacy against SARS-CoV-2 in animal models and human clinical trials, its mode of administration (intravenously) has limited its widespread use as it requires personnel and staff. qualified health facilities. Therefore, effective oral antiviral therapy or combination therapies which can be readily obtained from pharmacies and self-administered by the patient can have immense positive impacts on global public health.

A new study

Scientists have developed a nucleoside prodrug GS-621763 that can be administered orally. GS-621763 is an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, targeting highly conserved RdRp. Thus, this drug can metabolize inside cells and produce the same active nucleoside triphosphate formed by RDV. A new study published on bioRxiv* preprint server focused on in vitro antiviral activity in various cell models and in vivo therapeutic efficacy of oral GS-621763 in a mouse model of SARS-CoV-2 pathogenesis. A pre-printed version of the study is available on the bioRxiv * server, while the article is subject to peer review.

This study revealed that GS-621763 showed promising antiviral activity in lung cell lines and in two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile associated with oral administration of GS-621763 in mice infected with SARS-CoV-2 was studied. In the COVID-19 mouse model, GS-621763 has been reported to significantly lower viral load and improve severe lung disease and lung function. In addition, GS-621763 prevented the loss of body weight of the infected mice, which was not the case for the control group.

The researchers compared the effectiveness of GS-621763 with molnupiravir. Indeed, molnupiravir is also an oral nucleoside analogue antiviral drug and is currently undergoing clinical trials in humans. Interestingly, they observed that these two drugs have similar efficacy. Therefore, this study provided preclinical proof of concept data to show that the orally bioavailable ester analogue of RDV GS-621763 possesses antiviral effects against SAS-CoV-2. Therefore, the efficacy of GS-621763 for the treatment of COVID-19 in humans needs to be further validated in human clinical trials.

Conclusion and future research

Scientists are optimistic that oral antiviral therapies that target conserved viral proteins have optimal therapeutic utility against future emerging VoCs. The authors of this study aimed to determine the efficacy of combinations of antivirals in mouse models of the pathogenesis of SARS-CoV-2. They also aimed to understand the inhibition of transmission of the virus between animals, in other animal models, such as hamsters and ferrets. The present study provided preclinical data on an orally bioavailable nucleoside analogue prodrug, GS-621763. If this drug proves safe and effective in human clinical trials, it could help contain this pandemic and future outbreaks of CoV.

*Important Notice

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

Journal reference:

  • Schafer, A. et al. (2021) “Therapeutic efficacy of an oral nucleoside analog of remdesivir against the pathogenesis of SARS-CoV-2 in mice.” bioRxiv. doi: 10.1101 / 2021.09.13.460111.

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