An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS‐CoV M(pro)) Inhibitors

Al‐Gharabli, Samer I.; Shah, Syed T. Ali; Weik, Steffen; Schmidt, Marco F.; Mesters, Jeroen R.; Kuhn, Daniel; Klebe, Gerhard; Hilgenfeld, Rolf; Rademann, Jörg

A method for the parallel solid‐phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization‐free oxidation of amino alcohols with Dess–Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N‐protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS‐CoV M(pro)(also known as 3CL(pro)), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS‐CoV M(pro). Several potent inhibitors were found with IC(50) values in the low micromolar range. An IC(50) of 7.5 μm was found for AcNSTSQ‐H and AcESTLQ‐H. Interestingly, the most potent inhibitors seem to bind to SARS‐CoV M(pro) in a noncanonical binding mode.