Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an a-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
| Original language | English |
|---|---|
| Journal | Science |
| Volume | 368 |
| Issue number | 6489 |
| Pages (from-to) | 409-412 |
| Number of pages | 4 |
| ISSN | 0036-8075 |
| DOIs | |
| Publication status | Published - 24.04.2020 |
Funding
We thank Y. Kusov and G. Hansen, as well as A. Aljnabi, for determining the inhibitory activities of compounds in a SARS-CoV replicon and against recombinant MERS-CoV Mpro, respectively; T. Biet for recording 13C NMR spectra; A. Ahlers, J. Schreiber, and L. Litz for excellent technical assistance; K. Chen for continuous organizational support; and the staff at beamline 14.2 of BESSY II, Berlin, Germany, for help with diffraction data collection. Funding: We thank the German Center for Infection Research (DZIF) for financial support (projects TTU01, grant 8011801806, and TTU09, grant 8004709710). Author contributions: Conceptualization:
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
DFG Research Classification Scheme
- 2.11-01 Biochemistry
Coronavirus related work
- Research on SARS-CoV-2 / COVID-19
