A β-turn mimic and a thiomethylene dipeptide surrogate employed in the study of cyclic peptide RGD and RCD cell-adhesion inhibitors
✍ Scribed by Gilbert M. Rishton; Nancy K. Harn; Stephan J. Cripps; Shiu-Lan Chiang; Christy Mikos; Pina Cardarelli; Thomas J. Lobl; Frank Gorcsan; Mary Moscinski; Nancy G. J. Delaet; Sharon M. Walker
- Publisher
- Springer Netherlands
- Year
- 1996
- Tongue
- English
- Weight
- 536 KB
- Volume
- 3
- Category
- Article
- ISSN
- 1573-3149
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✦ Synopsis
During an inflammatory response, leukocytes adhere to the blood-vessel wall and to underlying extracellular matrix-protein fibronectin via noncovalent interaction through two distinct cell-surface integrins, ct5131 and ~4[~1. An Arg-Gly-Asp tripeptide in the cell-binding domain of fibronectin has been demonstrated to be the major site that mediates cell attachment. Our group has previously disclosed Arg-Gly-Asp-and Arg-Cys-Asp-containing cyclic peptide cell-adhesion inhibitors, which are potentially useful as anti-inflammatory agents, particularly in the treatment of asthma and rheumatoid arthritis. Subsequently, we have incorporated a 13-turn dipeptide mimic and a suitably protected Arg-Gly thiomethylene dipeptide surrogate into our lead peptides by solid-phase synthesis. The preparation of the surrogates, and the structure-activity studies of the surrogate-containing peptides are described in this paper. Complete loss of cell-adhesion inhibition activity was observed in the case of incorporation of the conformationally constrained p-turn dipeptide into a cyclic Arg-Cys-Asp peptide inhibitor. Incorporation of an Arg-Gly thiomethylene dipeptide surrogate into cyclic Arg-Gly-Asp and Arg-Cys-Asp cyclic disulfide peptide inhibitors was tolerated, resulting in cyclic pseudopeptide cell-adhesion inhibitors lacking the Arg-Gly peptide amide bond. *This paper is based on a presentation given at the Symposium on Peptide Structure and Design as part of the