Evaluation of the Antiviral Efficacy of Subcutaneous Nafamostat Formulated with Glycyrrhizic Acid against SARS-CoV-2 in a Murine Model.

Abstract

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.

• Authors: Ju Hwan Jeong, Woong Hee Lee, Seong Cheol Min, Beom Kyu Kim, On Bi Park, Santosh Chokkakula, Seong Ju Ahn, Sol Oh, Ji-Hyun Park, Ji Won Jung, Ji Min Jung, Eung-Gook Kim, Min-Suk Song
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 11 (May 31 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37298530 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• nafamostat
• Glycyrrhizic Acid

Topics

• Rats
• Humans
• Animals
• Mice
• SARS-CoV-2
• COVID-19
• Antiviral Agents (pharmacology, therapeutic use)
• Glycyrrhizic Acid (pharmacology, therapeutic use)
• Pandemics
• Disease Models, Animal
• Rats, Sprague-Dawley