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. 2020 Dec 15:889:173634.
doi: 10.1016/j.ejphar.2020.173634. Epub 2020 Oct 6.

Tissue distributions of antiviral drugs affect their capabilities of reducing viral loads in COVID-19 treatment

Yan Wang  1 , Lei Chen  2
Affiliations

Tissue distributions of antiviral drugs affect their capabilities of reducing viral loads in COVID-19 treatment

Yan Wang et al. Eur J Pharmacol. .

Abstract

Repurposing of approved antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising strategy to treat Coronavirus disease 2019 (COVID-19) patients. Previously we reported our hypothesis that the antiviral drugs with high lung distributions might benefit COVID-19 patients by reducing viral loads. So far, chloroquine, lopinavir, hydroxychloroquine, azithromycin, favipiravir, ribavirin, darunavir, remdesivir, and umifenovir have been tested in COVID-19 clinical trials. Here we validated our hypothesis by comparing the pharmacokinetics profiles of these drugs and their capabilities of reducing viral load in clinical trials. According to bulk RNA and single cell RNA sequencing analysis, we found that high expression of both angiotensin converting enzyme 2 (ACE2) and transmembrane Serine Protease 2 (TMPRSS2) makes the lung and intestine vulnerable to SARS-CoV-2. Hydroxychloroquine, chloroquine, and favipiravir, which were highly distributed to the lung, were reported to reduce viral loads in respiratory tract of COVID-19 patients. Conversely, drugs with poor lung distributions, including lopinavir/ritonavir, umifenovir and remdesivir, were insufficient to inhibit viral replication. Lopinavir/ritonavir might inhibit SARS-CoV-2 in the GI tract according to their distribution profiles. We concluded here that the antiviral drugs should be distributed straight to the lung tissue for reducing viral loads in respiratory tract of COVID-19 patients. Additionally, to better evaluate antiviral effects of drugs that target the intestine, the stool samples should also be collected for viral RNA test in the future.

Keywords: Antiviral drugs; Chloroquine; Coronavirus disease 2019; Favipiravir; Hydroxychloroquine; Tissue distribution.

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Conflict of interest statement

All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
RNA-seq analysis reveals transcript levels of ACE2, TMPRSS2 and CTSL genes in lung, intestine and kidney tissues. (A) Bulk RNA-seq data of mouse tissues are presented as mean ± S.E.M. (n = 4 biological replicates per tissue). Data source: PRJNA375882 (Yan et al., 2017). (B) Bulk RNA-seq data of human tissues. Data Sources: THE HUMAN PROTEIN ATLAS (Uhlen et al., 2015), available from https://www.proteinatlas.org. SI: Small intestine; LI: Large intestine (colon); NX: Normalized eXpression; pTPM: protein-coding transcripts per million. (C) The scRNA-seq data of human lung (Ziegler et al., 2020) and ileum (Ziegler et al., 2020) are visualized by Single Cell Portal - Broad Institute, available from https://singlecell.broadinstitute.org. The scRNA-seq data of human kidney (Liao et al., 2020) (GSE131685) are re-analyzed and visualized by Seurat (Butler et al., 2018; Stuart et al., 2019).
See this image and copyright information in PMC

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