A sweet pill to swallow: oral nucleoside analog of Remdesivir improved SARS-CoV-2 pathogenesis in mice

The coronavirus disease 2019 (COVID-19) pandemic has infected around 225 million people and claimed more than 4.64 million lives worldwide. This pandemic is caused by 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 SARS-CoV-2 pathogenesis 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 bodies, and in many countries, vaccination programs have commenced. Although the initial vaccination rate was extremely high in the US, recent reports have indicated that vaccination rates have fallen back due to vaccine hesitancy. In many other countries, sufficient vaccines are not available for the entire population, and hence, the vaccination process has been slow. These events fuel the surge in SARS-CoV-2 variants, many of which are more virulent than the original strain and can evade vaccine-induced immune responses and immunity gained after natural COVID-19 infection. Therefore, there is a need for oral antivirals to treat COVID-19 cases in unvaccinated and immunocompromised individuals. These antivirals could also be effective for the treatment of vaccine breakthrough cases.

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 long-term sequelae of COVID-19, and lower the hospitalization rate.

Therapies for COVID-19 disease

Several direct-acting antiviral (DAA) therapies are used for the treatment of COVID-19 patients, e.g., EUA-approved monoclonal antibodies (mAbs) and FDA-approved remdesivir (RDV, GS-5734). As all mAbs must be administered through injection, they cannot be readily used to treat patients. Also, some of the SARS-CoV-2 variants of concern (VoC) are resistant to the first line of mAb therapies. Many DAA such as nucleoside analogs molnupiravir (MPV, EIDD-2801), AT-527, and MPro inhibitor PF-07321332 are undergoing human clinical trials.

Advantages of nucleoside analog drugs

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

Even though previous research has described the therapeutic efficacy of RDV against SARS-CoV-2 in animal models and human clinical trials, its mode of administration (intravenous) has limited its widespread usage as it requires qualified health care staff and facilities. Hence, an effective oral antiviral therapy or combination therapies that can be easily obtained from the pharmacy 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 parental nucleoside of remdesivir, targeting the highly conserved RdRp. Thereby, 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 preprint version of the study is available on the bioRxiv* server, while the article undergoes peer review.

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

Researchers compared the efficacy of GS-621763 with molnupiravir. This is because molnupiravir is also an oral nucleoside analog antiviral and is currently undergoing human clinical trials. Interestingly, they observed that both these drugs possess similar efficacy. Therefore, this study provided proof-of-concept preclinical data to show that the orally bioavailable ester analog of RDV GS-621763 possesses antiviral effects against SAS-CoV-2. Hence, the efficacy of GS-621763 for treating COVID-19 in humans must be further validated in human clinical trials.

Conclusion and future research

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

*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.