(M1330-10-59) Determining the Efficacy and Toxicity Profile of Potential Oral Therapeutics Against SARS-CoV-2 in Mice

Purpose: The purpose of this study was to test the in vivo efficacy and toxicity of potential antiviral oral therapeutics SM-4 and SM-19 identified by our Artificial Intelligence DeepDrug software against SARS‑CoV-2, the causative agent of COVID-19, in the ACE2 mouse model.

Methods: Six hours following challenge with 5 x 103 TCID50 SARS-CoV-2, human transgenic female K18-hACE2 (B6.Cg-Tg(K18-ACE2)2PrlmnJ) mice were administered placebo, SM-4 at 50 mg/kg po or SM-19 50/100 mg combination once a day for 6 consecutive days at which time the animals were humanely sacrificed. The concentration of virus in lungs was determined by RT-qPCR assay. Briefly, RNA was extracted from samples stored in RNA/DNA Shield using the Quick-RNA Viral Kit (Zymo Research) according to manufacturer’s protocol. RT-qPCR was performed using the following RT-PCR cycling conditions: 50°C for 15 min (RT), then 95 °C for 2 min (denature), then 40 cycles of 10s at 95°C, 45s at 62°C. Primers used for SARS-CoV-2 detection: 2019-nCoV_N1-F 5’-GACCCCAAAATCAGCGAAAT-3’ 2019-nCoV_N1-R 5’-TCTGGTTACTGCCAGTTGAATCTG -3’ Probe: 2019-nCoV_N1-P: 5’-FAM-ACCCCGCATTACGTTTGGTGGACC-BHQ1-3’. Additional Experimental endpoints were also determined including body weight and body weight change and clinical chemistry determinations such as BUN, AST, and ALT.

Results: SM-4 and SM-19 treatment resulted in a 44.2% and 42.3% reduction in lung viral load compared to non-treated placebo control respectively (Table 1). There were no significant differences in body weight and all clinical chemistry determinations evaluated (i.e., kidney and liver enzymes) between the different treatment groups.

Conclusion: Taken together these preliminary findings suggest that these novel compounds may have significant in vivo activity against SARS CoV2 at non-toxic doses.

References: Bess A, Berglind F, Mukhopadhyay S, Brylinski M, Griggs N, Cho T, Galliano C, Wasan KM. Artificial intelligence for the discovery of novel antimicrobial agents for emerging infectious diseases. Drug Discov Today. 2022 Apr;27(4):1099-1107. doi: 10.1016/j.drudis.2021.10.022Acknowledgements: Funding for this Project was provided by Skymount Medical Inc.Table 1. LUNG RT-qPCR Data for SARS-COV-2 Virus following 6 days of treatment in Human Transgenic Infected female K18-hACE2 (B6.Cg-Tg(K18-ACE2)2PrlmnJ) mice administered either SM-4 50 mg/kg po or SM-19 drug combination 50/100 mg po once daily for 6 consecutive days.