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

Abstract

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.

Large Cyclic Peptides as Cores of Multivalent Ligands: Application to Inhibitors of Receptor Binding by Cholera Toxin

“…Final cleavage and HPLC purification gave the desired cyclic decapeptides 2 − 4 in satisfactory yields (24−30%). Although there have been reports of lower yields of formed cyclic peptide for large ring systems with use of the allyl protection strategy, , this does not appear to be a problem in our hands because the yields of 2 − 4 compared favorably with the yields of cyclic peptides (48- to 87-atom rings) prepared with alternative strategies. ,

1 Synthesis of Head-to-Tail Cyclic Decapeptides

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Structure–Function Studies of Linear and Cyclized Peptide Antagonists of the GnRH Receptor

“…The synthesis of all linear peptides was performed on a Labortec SP650 semiautomatic synthesizer. The cyclic peptides D-23620, D-24236, D-24418, D-49141, D-49650, D-49651, and D-52391 were synthesized from adequate linear precursors according to the dilution principle (44). Cyclization of linear precursors was accomplished in 0.1 mM range by slow addition of the DMF-solved peptide into 100 ml DMF in the presence of DIPEA and HATU (3 equiv.…”

Methods for the Peptide Synthesis and Analysis

“…Once chain elongation is finished, the deprotection of both ends and subsequent cyclization and cleavage delivers the final cyclized product. Numerous amino acids have been used for side-chain anchoring, including Asx/Glx [220][221][222][223][224][225][226], Lys/Orn [220,227], Ser/Thr [220,228], Tyr [220,224,229], His [230,231], and Cys [232,233], on the usual supports and linkers for peptide synthesis. BAL anchoring: The original concept of the BAL linker [234,235] involves the attachment of a backbone amide nitrogen to an appropriate handle.…”