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The novel coronavirus SARS-CoV-2 has been identified as cause of the COVID-19 pandemic. The viral main protease (Mpro, also called 3CLpro) is involved in forming the viral replication complex and is an attractive target for antiviral therapy. Its crystal structure has now been elucidated by the research group of Professor Rolf Hilgenfeld at the University of Luebeck. Today, the results will be published in the leading journal "Science".
The crystal structure of the Mpro was solved at a resolution of 1.75 Å . The practical value of the structure elucidation is evident, for example, from the optimization of small-molecule alpha-ketoamide inhibitors by Rolf Hilgenfeld's group. The main goal of the optimization efforts was the improvement of the pharmacokinetic properties of the compounds. Crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way were elucidated as well, at high resolution (1.5 and 2.20 Å).
These structures form the basis for the further development of the compounds to antiviral drugs. In addition, the structures elucidated in this study can also contribute to the discovery of additional inhibitors. The path from an inhibitor to a drug requires many additional studies.
The main protease is a key enzyme in the life cycle of the coronavirus, as it processes the huge polyproteins, into which the viral RNA is initially translated after it has entered the interior of the human cell. The protease cuts 12 smaller proteins out of the polyproteins, which in turn are components of the replication complex involved in copying the viral RNA genome. "If we succeed in inhibiting the main protease, we can thus stop virus replication", Rolf Hilgenfeld explains.
Being a chemist and structural biologist, Hilgenfeld has worked on such inhibitors since 2013, right after the start of the outbreak of Middle-East Respiratory Syndrome (MERS) on the Arab peninsula, which is caused by another deadly coronavirus. Since then, he and his team developed and optimized inhibitors that block the main protease of all kinds of coronaviruses. "We even made sure that our compounds do also block bat coronaviruses, which had been discovered in China", says Hilgenfeld, who has been working on coronaviruses since 1998.
Prof. Rolf Hilgenfeld is the Director of the Institute of Biochemistry of the University of Luebeck. He is well known for his research in structural virology. During the SARS pandemic of 2003, he managed to publish the structure of the main protease and a preliminary inhibitor. From that time, Hilgenfeld has established close collaborations with Chinese research institutions. In 2016, his team elucidated the three-dimensional structure of the Zika virus protease. This served as a basis for the development of an antiviral compound.
Prof. Hilgenfeld and his colleagues report on the research results published now:
"Since January 11, 2020, my coworkers Dr. Linlin Zhang and Xinyuanyuan Sun and I have been wor-king feverishly on the elucidation of the three-dimensional structure of a key enzyme of the novel coronavirus, SARS-CoV-2. January 11 was the day when a Chinese research group published the nucleotide sequence of the SARS-CoV-2 RNA genome. Linlin and Xinyuanyuan identified the region in the viral genome that codes for the key enzyme, the so-called main or 3C-like protease, translated it from RNA to DNA, had a synthetic gene synthesized by a company, and expressed this gene in E. coli bacteria", says Rolf Hilgenfeld.
"By the end of January, we had managed to purify enough enzyme and grow crystals of it", says Linlin Zhang, "and on February 01, we took these crystals to the BESSY synchrotron in Berlin to irridiate them with strong X-radiation". The X-rays were diffracted by the crystal into tens of thousands of low-intensity X-rays, and the distribution and intensities of these diffracted X-rays contains the information on the localization of each and every atom in three-dimensional space. "A few hours later, I had the structure determined by using well-established mathematical approaches coded within advanced computer programs", says Linlin.
On the basis of the crystal structure of the main protease of the novel coronavirus, the group could turn a lead compound developed earlier in the lab into a potent inhibitor of the novel coronavirus. Named "13b", the new compound was synthesized by Dr. Daizong Lin, a former postdoc of Rolf Hilgenfeld and now research director of a small company in Changchun, China.
"Our synthetic work was somewhat delayed by the shutdown of public life in China, which was necessary to combat the novel coronavirus", says Daizong. But by mid-February substantial amounts of the inhibitor were available and were sent to Dr. Katharina Rox at the Helmholtz Center of Infection Research in Braunschweig, Germany. She studied the behavior of the compound in healthy mice and showed that it was not toxic and best administered through injection under the skin or through inhalation.
When inhaled, substantial concentrations of "13b" accumulate in the lung after 24 hours, i.e. those organs most strongly affected by the virus in humans. Next, Prof. Stephan Be-cker and Dr. Lucie Sauerhering from the University of Marburg tested 13b in cultures of human lung cells infected with the novel coronavirus and found that it was active.
What are the next steps?
"Now, our inhibitor will have to be developed into a drug", explains Rolf Hilgenfeld. "For that, we have to get a pharmaceutical company onboard, because only them have the resources to finance clinical trials". He expects support from a consortium of companies and public research institutions (a private-public partnership) that is currently being formed as part of an initiative of the European Commission to fight the novel coronavirus. "But for sure, it will take several years until our inhibitor will be turned into an anti-coronaviral drug", cautions Hilgenfeld. "Everything going well, such a drug could be available for SARS-CoV-3, but certainly not during the current outbreak". And he adds: "In any case, we must uncouple antiviral research from the recurrent outbreaks of emerging viruses such as SARS-CoV-2 and make sure that we achieve a more sustainable drug development".
Prof. Hilgenfeld's research is financially supported by the German Center for Infection Research (DZIF) and, from April 01, by the European Commission.
Photo: Along with this press release, we provide a photo of Prof. rolf Hilgenfeld's research group. Contact: presse@uni-luebeck.de
http://science.sciencemag.org/lookup/doi/10.1126/science.abb3405
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