Inhibitors based on approved drugs and designed to disrupt the SARS-CoV-2 viral protein Mpro display strong antiviral activity both in vitro and in a transgenic mouse model, a new study reports. While vaccines are an important tool in the fight against COVID-19, it remains a high priority to develop antiviral drugs, especially with the rise of variants that may partially evade vaccines.
The viral protein Mpro is a protease that is required for cleaving precursor polyproteins into functional viral proteins. This essential function makes it a key drug target. Jingxin Qiao et al. designed 32 inhibitors based on either Boceprivir or Teleprovir, both of which are protease inhibitors approved to treat hepatitis C virus.
Six compounds protected cells from viral infection with high potency and two of these were selected for in vivo studies based on pharmacokinetic experiments. In a SARS-CoV-2 infection transgenic mouse model, treatment with both compounds greatly reduced lung viral loads and lung lesions.
Both also displayed good pharmacokinetic properties and safety in rats. The work in this paper "represents an important step toward the development of orally available anti-SARS-CoV-2 drugs," the authors say.
Qiao, J., et al. (2021) SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model. Science. doi.org/10.1126/science.abf1611.