key: cord-0685148-mybhsvo2
authors: Murakami, Eisuke; Bilello, John; Li, Ruidong; Li, Li; Porter, Danielle; Humeniuk, Rita; Mackman, Richard; Cihlar, Tomas; Osinusi, Anu; Feng, Joy
title: Reply to Yan and Muller, “Single-Cell RNA Sequencing Supports Preferential Bioactivation of Remdesivir in the Liver”
date: 2021-09-17
journal: Antimicrobial agents and chemotherapy
DOI: 10.1128/aac.01394-21
sha: 6d2d36f7f39cc6450d14dc41bab92f0f5726c930
doc_id: 685148
cord_uid: mybhsvo2

In their commentary "Single-Cell RNA Sequencing Supports Preferential Bioactivation of Remdesivir in the Liver", Yan and Muller state that two key pieces of data were misrepresented in our recent article titled "Key Metabolic Enzymes in Remdesivir Activation in Human Lung Cells." We would like to thank Yan and Muller for careful review of our publication and would like to address their comments as follows.….

is largely restricted to alveolar macrophages" made by Yan and Muller was based on a more limited data set from the Human Protein Atlas (HPA), where the human lung scRNAseq data only included 4,599 cells from a public data set, with an average of 548 genes and 940 UMIs detected per cell (https://www.proteinatlas.org/about/assays1 annotation) (4) . This data set has lower sensitivity and is more likely to result in false negatives for the purpose of the intended analysis. Importantly and as pointed out above, the efficiency of RDV activation cannot be judged solely by the enzyme expression levels, and the specific catalytic efficiency of each enzyme participating in the activation of RDV needs to be also taken into account. In addition, it is not presently clear how the intracellular activation of RDV is affected by levels of activating enzymes in different cell types and what absolute level of each enzyme is sufficient to generate effective intracellular triphosphate concentrations to inhibit SARS-CoV-2 replication.

Finally, RDV continues to be the only approved direct antiviral for hospitalized COVID-19 patients. Data from randomized clinical trials, including ACTT-1, demonstrated that RDV is associated with clinical benefits (5) . Emerging data, including the recently presented real-world evidence from almost 100,000 hospitalized patients, the largest RDV data set analyzed so far, shows that RDV is associated with clinical benefits, including a significant reduction in mortality rate (6) (7) (8) . As such, these clinical data sets support the underlying premise that there is effective metabolism of RDV in the target tissues relevant for SARS-CoV-2 replication.

Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

A molecular cell atlas of the human lung from single-cell RNA sequencing

A cellular census of human lungs identifies novel cell states in health and in asthma

Remdesivir for the treatment of Covid-19 -final report

Comparative effectiveness of remdesivir treatment in patients hospitalized with COVID-19

Remdesivir vs. standard of care for severe COVID-19

Remdesivir treatment is associated with improved survival in hospitalized patients with COVID-19

Key metabolic enzymes involved in remdesivir activation in human lung cells