Remdesivir (R), once incorporated into RNA (top panel), is rapidly removed by SARS-CoV-2 exonuclease (middle panel); however, in the presence of the exonuclease inhibitor Pibrentasvir, the incorporated Remdesivir is largely protected from excision (lower panel). These results were obtained using a mass spectrometry assay. The upper panel shows the RNA containing Remdesivir (red R) along with an image of a mass spectrum, showing intact RNA as the main peak. In the middle panel, the RNA is treated with exonuclease, which results in removal of nucleotides and Remdesivir from the RNA, as indicated by smaller RNA fragment peaks and the loss of the intact RNA peak. However, in the presence of Pibrentasvir, which inhibits the exonuclease, the RNA remains intact (lower panel), with the mass spectrum resembling that in the upper panel. This result might explain why Remdesivir by itself has limited efficacy for COVID-19 because of its rapid removal by the viral exonuclease. However, when the exonuclease is inhibited, because the Remdesivir remains, a more potent effect on viral replication is observed, as described in the publication.