Just Published in Metallomics

Authors: Dominic Graf, Nikolas Farn, Jonas Klopf, Mahniya Hojjati, Ulrich Schatzschneider*

Abstract: The 3-chymotrypsin-like protease 3CL^pro from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a potential target for antiviral drug development. In this work, three organometallic ferrocene-modified quinolinones and coumarins were compared to their benzoic acid ester analogues with regard to inhibition of 3CL^pro using an HPLC-based assay with a 15mer model peptide as the substrate. In contrast to FRET-based assays, this allows direct identification of interference of buffer constituents with the inhibitors, as demonstrated by the complete abolishment of ebselen inhibitory activity in the presence of dithiothreitol as a redox protectant. The presence of the organometallic ferrocene moiety significantly increased the stability of the title compounds towards hydrolysis. Among the studied compounds, 4-ferrocenyloxy-1-methyl-quinol-2-one was identified as the most stable and potent inhibitor candidate. IC₅₀ values determined for ebselen and this sandwich complex compound are (0.40 ± 0.07) and (2.32 ± 0.21) μM, respectively.

Link: https://academic.oup.com/metallomics/article-abstract/15/5/mfad023/7127704