UV-4B potently inhibits replication of multiple SARS-CoV-2 strains in clinically relevant human cell lines

Abstract

Background: SARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic. Although it poses a substantial public health threat, antiviral regimens against SARS-CoV-2 remain scarce. Here, we evaluated the antiviral potential of UV-4B, a host targeting antiviral, against SARS-CoV-2 in clinically relevant human cell lines. Methods: Cells derived from human lung (A549 cells transfected with human angiotensin converting enzyme 2 receptor (ACE2; ACE2-A549)) and colon (Caco-2) were infected with either a wild type or beta variant strain of SARS-CoV-2 and exposed to various concentrations of UV-4B. Supernatant was sampled daily and viral burden was quantified by plaque assay on Vero E6 cells. Results: Therapeutically feasible concentrations of UV-4B inhibited the replication of the wild type strain in ACE2-A549 and Caco-2 cells yielding EC50 values of 2.694 and 2.489 µM, respectively. UV-4B's antiviral effect was also robust against the beta variant in both cell lines (ACE2-A549 EC50: 4.369 µM; Caco-2 EC50: 6.816 µM). Conclusions: These results highlight UV-4B's antiviral potential against several strains of SARS-CoV-2.

Within-host virus evolution during the extended treatment of RSV infection with mutagenic drugs

“…The clearance of infection is therefore not a necessary condition for treatment to be of clinical value, albeit that further work would be required to establish the general clinical benefit of antiviral therapies short of viral clearance. Where ribavirin was responsible for a change in viral mutation rate, favipiravir did not confer a significant additional benefit, with insufficient dosing being one possible explanation (Franco et al, 2022).…”

Why Molnupiravir Fails in Hospitalized Patients

“…Vero E6 cells were purchased from the American Type Culture Collection (ATCC CRL-1586) and ACE2 transfected A549 cells (ACE2-A549 cells) ( 43 ) were a kind gift from Shinji Makino at the University of Texas Medical Branch. Both cell lines were maintained as previously described ( 44 , 45 ) and subcultured twice weekly to ensure subconfluency. The USA-WA1/2020 SARS-CoV-2 strain was obtained through Biodefense and Emerging Infectious Research Resources Repository (BEI Resources, NR-52281), and viral stocks were propagated on Vero E6 cells ( 45 ).…”

“…Antiviral assays employing static drug concentrations for molnupiravir, EIDD-1931, remdesivir, and GS-441524 were conducted in 6-well plates with ACE2-A549 cells and performed as previously described ( 44 ). Five drug concentrations were evaluated per compound along with a no-treatment control.…”

Investigational New Drug Enabling Nonclinical Safety Assessment of the Iminosugar UV-4, a Broad-Spectrum Host-Targeted Antiviral Agent

“…Other effects are generally consistent across species and are predictable with respect to dose, and the PK and TK data indicate good absorption after dosing with the hydrochloride salt. Recent publications have highlighted the potential importance for iminosugars including UV-4 as therapeutics for SARS-COV2, 31,32 and have positioned orally-bioavailable, broadspectrum, host-targeted antiviral therapeutics as a critical component for combatting future pandemics. 6 Therefore, UV-and critically revised manuscript; Sampath, A. contributed to conception and design, contributed to analysis and interpretation, and critically revised manuscript; Warfield, K.L.…”