Posted by A recent publication written by a team of University of Debrecen reported that the excipient, sulfobutylether-betadex (SBECD), in Veklury® (remdesivir by Gilead Sciences) was found to provide an additional function besides acting as potent solubilizer. (1) The SBECD-enabled remdesivir formulation – due to its high SBECD content – showed a so far unexpected additional benefit that further potentiates the antiviral efficacy of the product. We all remember that during the early phase of Covid-19 pandemy, the only therapy against SARS-CoV-2 virus was Veklury® infusion, approved by FDA and EMA, before the vaccines were introduced. Due to the poor water solubility of remdesivir substance, in both the powdery and liquid formulations large amounts of the SBECD solubilizing agent was applied, in order to attain a clinically relevant, stable parenteral formulation. This also means that patients treated with Veklury® received massive amounts of SBECD excipient, intravenously. The team of the Biophysical and Cell Biological Department of the Medical University of Debrecen, have reported for the first time that besides the known antiviral effect of the remdesivir, the applied solubilizer, the cyclodextrin derivative, also contributes to the antiviral efficacy of the Veklury® product. It was assumed and experimentally proven that SBECD has its own antiviral potency because – similarly to other beta-CD derivatives – it also interacts with lipid rich membrane domains (lipid rafts) of recipient cells and so indirectly inhibits virus internalization into the cells, thus contributes to the antiviral effect of Veklury. It has long been known that these lipid rafts on cell membrane are the entrance gates for SRS-CoV-2 viruses as their spike proteins land onto and bind to the ACE2 receptors. (2)
As the SBECD disintegrates the lipid packing around ACE2 protein, the virus landing becomes hindered. Flow-cytometry measurements indicated that both lipid-depleting cyclodextrins and Veklury® formulations reduced in a dose- dependent manner the binding of fluorescent-labeled Wuhan-Hu-1, delta- and omicron- variant spike proteins to ACE2 receptor protein. This phenomenon was proved by confocal microscopy and three-dimensional quantitative picture analyses. Authors described a new, possible antiviral effect of Veklury® formulations as they – due to their remdesivir content – not only inhibited RNA-dependent RNA polymerase intracellularly, but also prevented the adherence /landing of SARS-CoV-2 spike protein to cell membrane- anchored ACE2 receptor. These experimental results do have clinical relevance and draw the attention of clinicians to the benefits of such cyclodextrin-enabled APIs in clinical practice in the therapy against COVID-19 and other viral infections. This is the first time to report on the „effector function” of a solubilizing cyclodextrin excipient in antiviral therapy.
Reference:
- Tamas Kovacs et al. Veklury® (remdesivir) formulations inhibit initial membrane-coupled events of SARS-CoV-2 infection due to their sulfobutylether-β-cyclodextrin content. British Journal of Pharmacology 2023, 180, 2064-2084 https://doi.org/10.1111/bph.16063
- Joerg Gendle et al: Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2. Virology 2008, 381(2): 215–221. https://doi.org/10.1016/j.virol.2008.08.026