Type II transmembrane serine proteases (TTSP)

TMPRSS2

Patrick Müller, Hannah Maus, Stefan Hammerschmidt

Due to its fast international spread and its substantial mortality, the coronavirus disease COVID-19 evolved to a global threat. Since currently there is no causative drug against this viral infection, science is striving for new drugs and approaches to treat the new disease. Studies have shown that the cell entry of coronaviruses into host cells takes place through binding of the viral spike (S) protein to cell receptors. Priming of the S protein occurs via hydrolysis by different host proteases (furin, cathepsin L, TMPRSS2 etc.). The inhibition of these proteases could impair the processing of the S protein, thereby affecting the interaction with the host-cell receptors and preventing virus cell entry. Hence, inhibition of these proteases could be a promising strategy for a treatment against SARS-CoV-2.

Figure 1: Schematic overview of the viral cell entry.

In cooperation with the research group of Prof. V. Mailänder we focus on the design of novel peptidomimetic TMPRSS2 inhibitors. Molecular modeling studies resulted in tripeptides that are synthesized and linked with an electrophilic serine trap (warhead) to create covalent inhibitors. The compounds are tested against the serine protease matriptase (surrogate enzyme) and other different enzymes to accomplish high  affinity and selectivity. Stabilitiy assays are perfomed in blood serum, plasma and cell medium to evaluate the pharmacokinetic properties. Additionally, the antiviral effect of the most promising inhibitors are tested in CaCo-2 cells, which serve as a model for the human intestinal tract.

Figure 2: Development of peptidomimetic inhibtors. A: Computational modeling of potential binders. B: Synthesis of the covalent inhibitors. C: Validation of inhibitory effect of the synthesized compounds by bio-assays, e.g. fluorimetric AMC-assay.