Scientists build a foundation for drug discovery against COVID-19
Being able to live a normal life – going grocery shopping and taking leisurely walks around the park – is everyone’s dream these days. To everyone’s wishes, there just might be a breakthrough in overcoming the new pandemic, with the help of Dr. Hilgenfeld and his team of researchers.
Dr. Hilgenfeld discovered 3D structure of an enzyme essential in viral replication of the new coronavirus as well as developing a compound that could help in treating COVID-19.
Virus replicates itself by producing proteins inside the host cell. When viral proteins are first produced, they are processed by an enzyme called main protease. Resulting proteins then become a component in replicating RNA genome of the virus.
Main protease is an essential enzyme in viral life cycle because it processes a newly produced protein into smaller ones necessary for survival. Viral activity is significantly lower when main protease fails to function normally.
Researchers predicted that protease structure of new coronavirus would be similar to that of Severe Acute Respiratory Syndrome (SARS) virus. However, they could not identify the specific structure until recently.
When Dr. Hilgenfeld’s group analyzed protein structure of the new coronavirus by using X-ray, they found that protease structure of the new virus is mostly identical to that of SARS virus, with only few differences. They also designed a compound that inhibits main protease activity.
This new compound is derived from α-ketoamide inhibitors, which are used to treat SARS virus. It has been reported that an improved version of α-ketoamide inhibitors suppress viral replication activity in cells infected with new coronavirus. Decrease in viral replication activity led to a fewer number of infected cells Scientists led by Dr. Hilgenfeld further tested their newly developed compound in mice and observed that it was tolerated well. This means that the new compound does not cause adverse effects such as toxicity, whereas other medicines used to treat Ebola and HIV are still struggling with side effects.
Dr. Hilgenfeld explained that he hopes to “provide a framework for development of α-ketoamide inhibitors against new coronavirus.”
Zhang L, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020 Mar 20. (https://science.sciencemag.org/content/early/2020/03/20/science.abb3405.long)