Attractive target for drug against coronavirus
HZI researchers test active substance against SARS-CoV-2 developed in Lübeck
The new coronavirus SARS-CoV-2 has been identified as the pathogen behind the COVID-19 pandemic. The virus contains a main protease termed Mpro (or also termed 3CLpro), which is involved in the development of the virus’ replication complex. It consequently forms a part of the virus’ replication process and is an attractive drug target. A research group led by Prof. Rolf Hilgenfeld at Lübeck University and the German Center for Infection Research (DZIF) has now determined the protease’s crystal structure.
The crystal structure of the enzyme Mpro was identified at a resolution of 1.75 Angstroms. An Angstrom is a unit of length equal to one ten-millionth of a millimetre. Mpro is a key enzyme in the coronavirus’ life cycle as it processes polyproteins that are translated from the viral RNA once the virus has entered human cells. “If we succeed in blocking this main protease, we will be able to inhibit viral replication,” Prof. Rolf Hilgenfeld explains.
Using the main protease’s crystal structure Hilgenfeld changed a previously developed lead substance into a potent inhibitor of the new coronavirus. The resulting alpha-ketoamide complex, termed "13b", was synthesised by Dr Daizong Lin, a former postdoc of Prof. Hilgenfeld who is now Director of Research at a small company in Changchun, China.
“The synthesis work required to fight the new coronavirus was slightly slowed due to the shutdown of public life in China,” says Daizong. Nonetheless, by mid-February larger amounts of the inhibitor could be made available and were delivered to Dr Katharina Rox, a DZIF scientist at the Helmholtz Centre for Infection Research in Brunswick. She investigated the complex’s behaviour in healthy mice and showed that it is not toxic and is ideally administered by injection under the skin or by inhalation.
A sufficient concentration of “13b” accumulates in the lung, i.e. in the organ which is most affected by the virus in humans. Subsequently, DZIF scientist Prof. Stephan Becker and Dr Lucie Sauerhering, a member of Becker’s research team at Marburg University, tested 13b in cultures of human tongue cells that were infected with the new coronavirus and found that the bond was active.
“Now, the agent needs to be developed into a drug,” Rolf Hilgenfeld explains, “which will certainly take several years.”
Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Ute Curth, Christian Drosten, Lucie Sauerhering, Stephan Becker, Katharina Rox, Rolf Hilgenfeld. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors. Science 2020, DOI: 10.1126/science.abb3405.05.
Prof. Rolf Hilgenfeld