Native-like cyclic peptide models of a viral antigenic site: finding a balance between rigidity and flexibility

Abstract

Antigenic site A of foot-and-mouth disease virus (serotype C) has been reproduced by means of cyclic versions of peptide A15, YTASARGDLAHLTTT, corresponding to residues 136-150 of envelope protein VP1. A structural basis for the design of the cyclic peptides is provided by crystallographic data from complexes between the Fab fragments of anti-site A monoclonal antibodies and A15, in which the bound peptide is folded into a quasi-cyclic pattern. Head-to-tail cyclizations of A15 do not provide peptides of superior antigenicity. Internal disulfide cyclization, however, leads to analogs which are recognized as one to two orders of magnitude better than linear A15 in both ELISA and biosensor experiments. CD and NMR studies show that the best antigen, CTASARGDLAHLTT-Ahx-C (disulfide), is very insensitive to environment-induced conformational change, suggesting that cyclization helps to stabilize a bioactive-like structure.

Antigenicity modulation upon peptide cyclization: application to the GH loop of foot-and-mouth disease virus strain C1-Barcelona

“…As reported earlier for the linear (A15S8c1) and cyclic disulfide (AhxA16SS) versions of FMDV C-S8c1 [14,28], the conformational chemical shifts in the region that includes the RGD tripeptide are compatible with an open turn conformation. Further, the cluster of negative conformational chemical shifts from 143 Asp to 146 His could be suggestive of an incipient short helix in this region, as also reported for the C-S8c1 peptides [14,28]. A difference between the peptides of both strains is, however, the fact that this short helix extends, in the C-S8c1 peptides, to the 147 Leu residue.…”

“…The usefulness of cyclization as a means to enhance the antigenicity of peptides that, in the linear form, do not suitably reproduce the antigenic behavior of the native antigen has been generally acknowledged [14,[29][30][31][32][33]. In this work, we have successfully applied the cyclization approach to the GH loop of FMDV C-S30 and found an improvement of two orders of magnitude in the recognition by mAb 4C4 relative to the linear form.…”

“…In view of these unexpected results, we studied the A15S30 -mAb interaction in solution by means of a solution affinity SPR experiment. Finally, as done earlier for a C-S8c1-derived peptide [14], we have introduced conformational restrictions in the C-S30 loop, by means of an intramolecular disulfide bridge. The resulting cyclic peptide reproduces to a good extent the SPR binding behavior expected from earlier data, and its structural analysis by 2D-1 H NMR is consistent with the adoption of a native-like conformation.…”

Fermented Soybean Products and Their Bioactive Compounds

“…In a previous design, while searching for lead peptide candidates, the efficacy of a design approach based on the use of a cyclic peptide as a model of linear analog was demonstrated (Valero, et al, 2000). The conformational behavior of the cyclic peptides showed that the 6-membered cyclic peptide was relatively stable compared to the 8-, and 10-membered cyclic peptides (Pak et al, 2010).…”

Unnatural Translation Initiation

“…Cyclic peptides are of interest because of their increased stability in biological systems and membrane permeability (4). They are more conformationally limited than linear peptides of identical sequence, resulting in a more rigid structure and, potentially, tighter target binding (5). Also, many biologically active natural products, such as vancomycin, have a cyclic peptide framework.…”