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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.
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