From peptide libraries to optimized nonpeptide ligands in the search for S‐farnesyltransferase inhibitors

Abstract

A complete 331,776-member library of tetrapeptides made of 24 amino acid building blocks was synthesized robotically on solid phase and subjected to a deconvolution based on the inhibitory potency of the sublibraries in a HPLC assay of the S-farnesyltransferase activity in vitro. One of the non-natural peptide and noncysteine-containing leads Nip-Trp-Phe-His (Nip=p-nitrophenyl-L-alanine) was optimized chemically to give a proteolytically stable pseudopeptide with a 200-fold potency compared with the original lead. The final compound was converted to the C-terminal ethyl ester: p-F-C6H4-CO(CH2)2-CO-Bta-D-Phepsi[CH2NH]His-OEt (Bta = benzothienyl-L-alanine) and shown to behave as a prodrug which was hydrolyzed back to the C-terminal acid following cell penetration. The method confirmed that several structurally original leads can be discovered in large libraries when deconvolution relies upon a highly specific assay and that these leads can be optimized by chemical modification to impart the final compound the desired pharmacological and pharmacokinetic properties.

NMR‐derived model of interconverting conformations of an ICAM‐1 inhibitory cyclic nonapeptide

“…Synthetic methods have been described for many peptide structural motifs, allowing the replacement of such motifs by nonpeptide moieties (30,31,38–40). In this way, the properties of high affinity and specificity can be transferred to a peptide mimetic, whose pharmacokinetic properties are more suitable for clinical use (31,41–43).…”

NMR solution structure of a potent cyclic nonapeptide inhibitor of ICAM‐1‐mediated leukocyte adhesion produced by homologous amino acid substitution

“…Synthetic methods have been described for many peptide structural motifs, allowing the replacement of such motifs by nonpeptide moieties (28,37–39). In this way, the properties of high affinity and specificity can be transferred to a peptidomimetic or nonpeptide organic, increasing potency and allowing for oral administration (28,40,41). The identification and structural elucidation of more potent peptide derivatives is a necessary first step in this process.…”