Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju-si 28644, Republic of Korea.
MODNBIO Inc., Seoul 08378, Republic of Korea.
Int J Mol Sci. 2023 May 31;24(11):9579. doi: 10.3390/ijms24119579.
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.
持续的 COVID-19 大流行凸显了有效抗病毒药物和疫苗的迫切需求。药物重定位，即通过修改现有的药物，为加快新型治疗药物的开发提供了一种很有前途的方法。在这项研究中，我们通过将甘草酸（GA）掺入现有的药物那屈肝素（NM）中来开发一种新药 MDB-MDB-601a-NM。我们评估了 MDB-601a-NM 和那屈肝素在 Sprague-Dawley 大鼠中的药代动力学特征，结果表明那屈肝素的清除速度很快，而 MDB-601a-NM 经皮下给药后药物浓度持续。单次毒性研究表明，MDB-601a-NM 高剂量给药时具有潜在毒性和注射部位持续肿胀。此外，我们使用 K18 hACE-2 转基因小鼠模型评估了 MDB-601a-NM 预防 SARS-CoV-2 感染的功效。与那屈肝素治疗组相比，用 60mg/kg 和 100mg/kg 的 MDB-601a-NM 治疗的小鼠体重减轻和存活率提高，显示出更好的保护作用。组织病理学分析显示，MDB-601a-NM 治疗组的组织病理学变化和抑制效果呈剂量依赖性改善。值得注意的是，当用 60mg/kg 和 100mg/kg 的 MDB-601a-NM 治疗时，在脑组织中未检测到病毒复制。我们开发的 MDB-601a-NM，一种含有甘草酸的改良那屈肝素，显示出对 SARS-CoV-2 感染的保护作用。它经皮下给药后的持续药物浓度和剂量依赖性改善使其成为一种有前途的治疗选择。
