| Autor: |
Gordon C. Tucker, Marc Bertrand, Armelle Loynel, Jean-Luc Fauchère, Jean-Michel Henlin, Annie Genton, C. Desmet-Beaufort, Jean A. Boutin, Ghanem Atassi, Nathalie Kucharczyk |
| Rok vydání: |
2001 |
| Předmět: |
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| Zdroj: |
The Journal of Peptide Research. 57:85-96 |
| ISSN: |
1397-002X |
| Popis: |
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-Pheψ[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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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