A comparative study of cyclization strategies applied to the synthesis of head-to-tail cyclic analogs of a viral epitope

• Published in: The journal of peptide research Vol. 53; no. 1; pp. 56 - 67
• Main Authors: Valero, M.-L., Giralt, E., Andreu, D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-01-1999
• Subjects: Antibodies, Monoclonal - metabolism; Aphthovirus - immunology; Capsid - immunology; Capsid Proteins; Chromatography, High Pressure Liquid; cyclic peptides; epitope peptides; Epitopes - chemistry; Epitopes - immunology; foot-and-mouth disease virus; Models, Molecular; Oligopeptides - chemical synthesis; Oligopeptides - immunology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - immunology; solid phase-mediated cyclization
• ISSN: 1397-002X; 1399-3011
• DOI: 10.1111/j.1399-3011.1999.tb01617.x

A family of head‐to‐tail cyclic peptide models of the antigenic site A (G‐H loop of viral protein 1) of foot‐and‐mouth disease virus has been designed on the basis of the three‐dimensional structure adopted by the linear peptide YTASARGDLAHLTTT upon binding to neutralizing monoclonal antibodies. Three different methods of cyclization have been examined to access the peptides. Solution cyclization of a minimally protected linear precursor provided the expected products but required several purification steps that lowered the yields to 10%. The two other approaches relied on side‐chain anchoring of the peptide through the Asp residue and cyclization on the solid phase. A synthetic scheme combining Fmoc, tBu and OAI protections was practicable but inefficient when scaled‐up. The combination of Boc, Bzl and OFm protections was more promising, but suffered from high epimerization during the initial esterification of Boc‐Asp‐OFm to benzyl alcohol‐type resins. This problem was solved by performing the esterification via the cesium salt of Boc‐Asp‐OFm. With this improvement, the Boc/Bzl/OFm has become the method of choice for the preparation of cyclic head‐to‐tail peptides in satisfactory yields and with minimal purification.