key: cord-0759556-zx3v96lr authors: Rosenke, Kyle; Hansen, Frederick; Schwarz, Benjamin; Feldmann, Friederike; Haddock, Elaine; Rosenke, Rebecca; Meade-White, Kimberly; Okumura, Atsushi; Leventhal, Shanna; Hawman, David W.; Ricotta, Emily; Bosio, Catharine M.; Saturday, Greg; Feldmann, Heinz; Jarvis, Michael A. title: Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model date: 2020-10-08 journal: Res Sq DOI: 10.21203/rs.3.rs-86289/v1 sha: 6818af7f6a073eec7b72595c98b987e83a7af8fe doc_id: 759556 cord_uid: zx3v96lr The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication was observed in animals when the drug was administered either beginning 12 hours before or 12 hours following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of 32 coronavirus disease 2019 (COVID-19) 1 . Following emergence of the virus in Wuhan in the Hubei 33 6 corresponded to a 2-log decrease in infectious virus in the lungs of the MK-4482 treated groups 106 when compared to the vehicle controls ( Figure 2D ). 107 Lung samples were taken for histopathological analyses, and results are shown in Figure 108 3A to F. Analysis revealed pulmonary lesions consisting of a moderate-marked broncho-109 interstitial pneumonia centered on terminal bronchioles and extending into the adjacent alveoli. were significantly less abundant. One animal in each of the pre-and post-infection treatment 120 groups had no lesions at all. Pneumonia in the remaining animals affected roughly 5-15% of the 121 lung tissue, but lesions were minimal to mild. 122 Immunoreactivity against SARS-COV2 antigen was used to further compare the lung 123 samples between the three different treatment groups ( Figure 3G to I). Antigen staining was 124 observed in bronchial and bronchiolar epithelium, type I and II pneumocytes as well as a small 125 number of pulmonary macrophages. A positive pixel analysis on whole lung slides demonstrated 126 a significant difference in viral antigen present among the three groups. The total number of 7 positive pixels was divided by the area of lung scanned to determine a percentage of lung 128 containing viral antigen. This analysis revealed that the vehicle controls contained significantly 129 more antigen than the treated groups, with the vehicle controls having on average 4.71 times 130 more antigen signal than pre-infection treatment animals and 3.68 times more signal than post-131 infection treatment animals. Post-infection treatment animals exhibited a slightly higher antigen 132 signal than pre-infection treatment animals, but the difference was not significant ( Figure 4A ). 133 To evaluate the pharmacokinetics of MK-4482 in the animals, MK-4482 and the EIDD-134 1931 metabolite were measured in clarified lung homogenate by liquid chromatography and 135 mass spectrometry (LCMS) at the point of necropsy. Since SARS-CoV-2 is a respiratory disease, 136 levels of drug in lung tissue are expected to be the best indicator of therapeutic potential. All 137 treated animals displayed detectable levels of EIDD-1931 In the present study, we used the established Syrian hamster animal model 16, 17 There was a significant difference in lung viral loads between the pre-infection group compared to the vehicle control. Although the post-infection group trended towards lower levels, there was no significant difference between this group and vehicle control. (D) Infectious titers in the lungs were significantly different between both pre-infection and post-infection groups, compared to vehicle control group, but no significance was found between treatment groups from each other. For B to D geometric means are shown. 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