A comparative study of cyclization strategies applied to the synthesis of head-to-tail cyclic analogs of a viral epitope.
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 approximately 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.
Valero
M L
ML
Department of Organic Chemistry, University of Barcelona, Spain.
Giralt
E
E
Andreu
D
D
D000911:Antibodies, Monoclonal / Q000378:metabolism; D005537:Aphthovirus / Q000276:immunology; D002213:Capsid / Q000276:immunology; D036022:Capsid Proteins; D002851:Chromatography, High Pressure Liquid; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000276:immunology
D000911:Antibodies, Monoclonal; D036022:Capsid Proteins; D000939:Epitopes; D009842:Oligopeptides; D010456:Peptides, Cyclic