Development of a new antiviral agent against SARS-CoV-2
The search for effective drugs against the new coronavirus is currently a top priority at the German Center for Infection Research (DZIF). Developing inhibitors of viral replication is a promising approach, for which reason DZIF scientists at the University of Lübeck are targeting a main protease, an important enzyme in SARS-CoV-2 which is responsible for viral replication. Recently, Prof. Rolf Hilgenfeld and his team succeeded in elucidating the main protease’s precise structure, and consequently fulfil the prerequisites for developing specific inhibitors.
“If we succeed in blocking this enzyme, i.e. the main protease, we will be able to stop viral replication,” explains Prof. Rolf Hilgenfeld from University of Lübeck, “which is the goal of our project.” Prof. Rolf Hilgenfeld is a chemist and structural biologist, and has been working on coronavirus inhibitors at the DZIF and other institutions since 2013. Hilgenfeld succeeded in turning a previously developed lead substance into a potent new coronavirus inhibitor based on the main protease’s crystal structure. Dr Katharina Rox at the Helmholtz Centre for Infection Research in Brunswick (HZI) further investigated this compound, a so-called alpha-ketoamide, so as to improve both its half-life and stability. Dr Rox heads the DZIF Pharmacokinetics and Pharmacodynamics (PK/PD) Unit.
Consequently, a second-generation inhibitor has been created. It is termed RHCDS-13b, is non-toxic in mice and distributes in the lungs, the target organ. These features form good prerequisites for further developing the substance into a drug, which is now being carried out in a DZIF study. DZIF researcher Prof. Stephan Becker and his team at University of Marburg have already been able to show that the agent inhibits the new coronavirus in Calu-3 human lung cells. The scientists from Lübeck now intend to synthesise larger quantities of the agent so as to test its pharmacokinetic properties in higher concentrations.
Dr Katharina Rox, who was also involved in testing the agent’s properties in mice during the optimisation phase, will be conducting these tests at the HZI. The tests will investigate the agents’ activity following intravenous, subcutaneous and inhalational administrations. “Amongst other things, these tests will reveal whether the inhibitor distributes well in the lungs, where it is most needed in the case of COVID-19,” Dr Rox explains.
The scientists from Lübeck also plan to synthesise other similar compounds which they had previously developed as so-called back up agents, and subsequently conduct similar tests on their antiviral effects against SARS-CoV-2. “We now urgently need to be in a position to sustainably develop antiviral agents,” emphasises Rolf Hilgenfeld. “Even though these inhibitors will not be available for this outbreak, their development is of major importance for future outbreaks.”
