title: An efficient method for the synthesis of peptide aldehyde libraries employed in the discovery of reversible SARS coronavirus main protease (SARS-CoV Mpro) inhibitors.
abstract: 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 muM 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.
authors: Leibniz Institut für Molekulare Pharmakologie (FMP), Department for Medicinal Chemistry, Berlin, Germany.
authors: Samer I
authors: SI
authors: Al-Gharabli
authors: Syed T Ali
authors: ST
authors: Shah
authors: Steffen
authors: S
authors: Weik
authors: Marco F
authors: MF
authors: Schmidt
authors: Jeroen R
authors: JR
authors: Mesters
authors: Daniel
authors: D
authors: Kuhn
authors: Gerhard
authors: G
authors: Klebe
authors: Rolf
authors: R
authors: Hilgenfeld
authors: Jörg
authors: J
authors: Rademann