Antiviral activity of lipid-modified remdesivir in comparison to common remdesivir

Remdesivir (RDV) is an adenosine nucleotide analog phosphoramidate prodrug that has a broad-spectrum antiviral activity. On October 22, 2020, FDA approved remdesivir for use in adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization.

In new research, scientists evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524) against viruses that cause diseases of human public health concern, including SARS-CoV-2.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

“While RDV did not significantly reduce COVID-19 mortality, it did shorten the time to recovery compared to a placebo control group”, says the team of researchers.

Recent studies suggested the utilization of RDV parent nucleoside (RVn) due to their high efficacy in vivo and also because, unlike RDV, their half-life is longer. One of the most prominent drawbacks of RDV is that it has to be administered intravenously, which makes it less suitable concerning hospital contexts

“In an attempt to develop an orally bioavailable form of remdesivir, we recently synthesized a 1-O-octadecyl-2-O-benzyl-sn-glycerylester (ODBG) lipid-modified monophosphate prodrug of RVn (ODBG-P-RVn), which demonstrated more favorable in vitro antiviral activity against SARS-CoV-2 compared to that of RVn and 43 RDV in Vero-E6 cells”, says the team.

This study focuses on comparing the antiviral activities of RDV, RVn, and ODBG-P-RVn against different viruses that are responsible for causing diseases that are of significant public health concern.

What did the study involve?

The study involved fourteen different viruses spread over seven different families against which the antiviral properties of RDV, RVn, and ODBG-P-RVn were tested. The different families of viruses involved in the study were: Paramyxoviridae, Flaviviridae, Pneumoviridae, Filoviridae, Nairoviridae, Arenaviridae, Coronaviridae.

Three different assays were performed to compare the activities of RDV, RVn, and ODBG-P-RVn; measurement of fluorescence of reporter protein that is expressed by the recombinant viruses, quantifying the focus-forming units by the help of fluorescence reporter imaging and indirect measurement of cytopathic effect which was based on the cellular ATP levels.

What did the study find?

The researchers found that the results of dose-response experiments against RDV, RVn, and ODBG-P-RVn in Vero-E6 cells comprising the panel of viruses showed that ODBG-P-RVn was more effective than RDV and RVn for all susceptible viruses.

“RVn and ODBG-P-RVn induced partial cytotoxicity but only at the highest concentration tested (100 µM) and without reaching 50% cytotoxicity (CC50)”, says the team.

The antiviral activities of RDV, RVn, and ODBG-P-RVn was further assessed in two human cell lines, bronchioalveolar carcinoma (NCI-H358) and human hepatoma (Huh7). It was found that ODBG-P-RVn showed three to five times greater antiviral activity than RVn, but it showed six to twenty times lesser activity as compared to RDV.

Further evaluation of cell-type-specific effects RDV, RVn, and ODBG-P-RVn were done using a smaller subset of filoviruses and a paramyxovirus. The results obtained were similar to those found in the human cell lines.

Although RDV was found to be the most effective antiviral agent but it showed more significant cytotoxicity compared to the other two agents. Experiments were also done in hTERT-immortalized 92 small airway epithelial cells (HSAEC1-KT) that yielded the same result.

What did the authors conclude?

“In summary, our results demonstrate that ODBG-P-RVn has greater antiviral activity than RVn in all cell 101 lines tested and has cell-type dependent activity levels that range from moderately lesser than to nearly equal to those of RDV”, says the team.

In vivo RDV rapidly converted to RVn whose antiviral activity is less than RDV, whereas ODBG-P-RVn is stable in plasma for more than 24 hours.

“Taken together, our results 108 strongly support the investigation of in vivo efficacy of ODBG-P-RVn not only against SARS-CoV-2 but also 109 against other viruses significant to human health”, added the team.

*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.

Journal reference:
Suchandrima Bhowmik

Written by

Suchandrima Bhowmik

Suchandrima has a Bachelor of Science (B.Sc.) degree in Microbiology and a Master of Science (M.Sc.) degree in Microbiology from the University of Calcutta, India. The study of health and diseases was always very important to her. In addition to Microbiology, she also gained extensive knowledge in Biochemistry, Immunology, Medical Microbiology, Metabolism, and Biotechnology as part of her master's degree.

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