Activity of Galidesivir in a Hamster Model of SARS-CoV-2

Abstract

Coronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.

Keywords: RNA viruses; SARS-CoV-2; antiviral; coronavirus; nucleoside analog.

Figure 1

Study design. SARS-CoV-2 infected animals were treated twice a day (BID) by intraperitoneal injection with galidesivir or the vehicle control. Oropharyngeal (OP) swabs were collected on Days 1, 2, and 3 post infection. Lung, turbinate, trachea, and heart tissues were collected on Days 3 and 7 post infection. There were eight animals per group; four animals per group were euthanized on Day 3, and the remaining four were euthanized on Day 7. Triangles represent schedule for BID treatments for Group 1 (lilac), Group 2 (orange), Group 3 (teal), and Control (brown). Purple circles represent OP swabs. Black X represents necropsy.

Figure 2

Mean weight change from Day 0 through Day 7. Statistical analysis was conducted using an ANCOVA model with terms for treatment and baseline value as covariates. ** p < 0.01, *** p < 0.001 for difference in adjusted least-square means compared with the control. SD, standard deviation; BID, twice daily dosing.

Figure 3

Mean viral burden (log₁₀) in OP swabs, turbinate, and lung tissues. (a) Replicative virus was detected by OP swabs from Day 1 through Day 3 across treatment groups. (b) Replicative virus in turbinate and lung tissues on Day 3 post infection. All groups receiving active treatment had lower viral burden in lung tissues relative to controls. Analysis of multiple comparisons was conducted with a One-way ANOVA with Dunnett’s test. PFU, plaque-forming unit; BID, twice daily dosing.

Figure 4

Paired profiles of viral burden in turbinate and lung tissue (n = 24). The analysis was conducted using a paired T-test, which compared the mean viral burden in turbinate and average lung tissue (average of cranial and caudal lung samples) from the same hamster. PFU, Plaque forming units.

Figure 5

Histopathology. Boxplots represent median, Q1, and Q3. The mean is indicated by a circle within the boxplot, and whiskers extend to minimum and maximum values. (a) Histopathology scores from lung, trachea, and heart tissues at Day 3 post infection. (b) Histopathology scores from lung, trachea, and heart tissues at Day 7 post infection. (c) Histopathology scores from lung, trachea, and heart tissues at Day 3 and Day 7 post infection combined. Statistical significance was tested using Dunnetts’ test for mean differences. * p < 0.05 compared to control. BID, twice daily dosing.

Figure 5

Histopathology. Boxplots represent median, Q1, and Q3. The mean is indicated by a circle within the boxplot, and whiskers extend to minimum and maximum values. (a) Histopathology scores from lung, trachea, and heart tissues at Day 3 post infection. (b) Histopathology scores from lung, trachea, and heart tissues at Day 7 post infection. (c) Histopathology scores from lung, trachea, and heart tissues at Day 3 and Day 7 post infection combined. Statistical significance was tested using Dunnetts’ test for mean differences. * p < 0.05 compared to control. BID, twice daily dosing.

Figure 6

Correlation analysis. Pearson’s correlation was used to measure the association of viral burden and histopathology total scores at each location for hamsters with both histopathology data and matching viral burden data at Day 3 (n = 16). Viral burden data were collected from OP swabs, lungs (combined cranial and caudal), and turbinates. Grey, OP swabs; Light blue, turbinates; Dark blue, lungs.