We have located links that may give you full text access.
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 Februrary 28
BACKGROUND AND PURPOSE: Despite its contradictory clinical performance, Veklury® (remdesivir) has a pivotal role in COVID-19 therapy. Possible contributions of the vehicle sulfobutylether-β-cyclodextrin (SBECD) to Veklury® effects are neglected and the powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane-coupled events of SARS-CoV-2 infection and highlight the cholesterol depletion-mediated active role of SBECD.
EXPERIMENTAL APPROACH: Using time-correlated flow cytometry and quantitative 3-dimensional confocal microscopy we studied early molecular events of SARS-CoV-2-host cell membrane interactions.
KEY RESULTS: Veklury® and different cholesterol-depleting cyclodextrins (CDs) reduced binding of the spike receptor binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan-Hu-1, Delta and Omicron variants. Correlations of these effects with cholesterol-dependent changes in membrane structure and decreased, lipid raft-dependent ACE2-TMPRSS2 interaction establish that SBECD is not simply a vehicle, but also an effector in Veklury® due to its cholesterol-depleting potential. Veklury® solution inhibited RBD binding more efficiently due to its two-times higher SBECD content. The CD-induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression suggesting that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low.
CONCLUSION AND IMPLICATIONS: Our findings call for the differentiation of Veklury® formulations in meta-analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant CD therapy, even at higher doses, in COVID-19.
EXPERIMENTAL APPROACH: Using time-correlated flow cytometry and quantitative 3-dimensional confocal microscopy we studied early molecular events of SARS-CoV-2-host cell membrane interactions.
KEY RESULTS: Veklury® and different cholesterol-depleting cyclodextrins (CDs) reduced binding of the spike receptor binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan-Hu-1, Delta and Omicron variants. Correlations of these effects with cholesterol-dependent changes in membrane structure and decreased, lipid raft-dependent ACE2-TMPRSS2 interaction establish that SBECD is not simply a vehicle, but also an effector in Veklury® due to its cholesterol-depleting potential. Veklury® solution inhibited RBD binding more efficiently due to its two-times higher SBECD content. The CD-induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression suggesting that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low.
CONCLUSION AND IMPLICATIONS: Our findings call for the differentiation of Veklury® formulations in meta-analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant CD therapy, even at higher doses, in COVID-19.
Full text links
Related Resources
Trending Papers
Challenges in Septic Shock: From New Hemodynamics to Blood Purification Therapies.Journal of Personalized Medicine 2024 Februrary 4
Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection.International Journal of Molecular Sciences 2024 April 4
The 'Ten Commandments' for the 2023 European Society of Cardiology guidelines for the management of endocarditis.European Heart Journal 2024 April 18
A Guide to the Use of Vasopressors and Inotropes for Patients in Shock.Journal of Intensive Care Medicine 2024 April 14
Diagnosis and Management of Cardiac Sarcoidosis: A Scientific Statement From the American Heart Association.Circulation 2024 April 19
Essential thrombocythaemia: A contemporary approach with new drugs on the horizon.British Journal of Haematology 2024 April 9
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app