Meisoindigo: An Effective Inhibitor of SARS-CoV-2 Main Protease Revealed by Yeast System

The COVID-19 pandemic caused by SARS-CoV-2 has had a significant impact on global health and the global economy. Despite the availability of vaccines, limited accessibility and vaccine hesitancy pose challenges in controlling the spread of the disease. Effective therapeutic strategies, including antiviral drugs, are needed to combat the future spread of new SARS-CoV-2 virus variants. The main protease (Mpro) is a critical therapeutic target for COVID-19 medicines, as its inhibition impairs viral replication. However, the use of substances that inhibit Mpro may induce selection pressure. Thus, it is vital to monitor viral resistance to known drugs and to develop new drugs. Here, we have developed a yeast system for the identification of Mpro inhibitors as an alternative to costly and demanding high-biosecurity procedures. The system is based on stable expression of Mpro and does not require selection media. Yeast can be cultured on a rich carbon source, providing rapid growth and screening results. The designed tool was subsequently used to screen the FDA-Approved Drug Library. Several chemicals with Mpro inhibitory properties were identified. We found that meisoindigo, which was not previously known to have the potential to inhibit Mpro, was highly effective. Our results may promote the development of new derivatives with therapeutic properties against SARS-CoV-2 and other beta-coronaviruses.