Structural comparison between retro-inverso and parent peptides: Molecular basis for the biological activity of a retro-inverso analogue of the immunodominant fragment of VP1 coat protein from foot-and-mouth disease virus

Abstract

Antibodies induced against intact foot‐and‐mouth disease Virus (FMDV) particles bind to the retro‐inverso analogue of fragment 141–159 of the viral coat protein VP1 of FMDV, variant A, equally well as to the parent peptide. A conformational investigation of this retro‐inverso peptide was carried out by nmr spectroscopy and restrained molecular modeling in order to identify the structural basis for the antigenic mimicry between these retro‐inverso and parent peptides. In 100% trifluoroethanol a well‐defined left‐handed α‐helical region exists from residue 150 to residue 159, which is consistently present in all conformational families obtained from restrained modelling. A less‐defined left‐handed helical region is present in the tract 144–148, which is also consistent for all structures. Conformational flexibility exists about Gly149, which leads to two types of structures, either bent or linear. In the bent structures, a three‐residue inverse tight turn is found, which can be classified as an inverse γ‐turn centered at Gly149. The overall structural features of the retro‐inverso peptide are shown to be similar to those of the parent L‐peptide. The two molecules, however, are roughly mirror images because they share inherently chiral secondary structure elements. By comparing these conformational conclusions with the x‐ray structure of the Fab complex of a corresponding VP1 antigenic fragment, a rationale is proposed to account for the topological requirements of specific recognition that are implied by the equivalent antigenic activity of the natural and retro‐inverso compounds. © 1997 John Wiley & Sons, Inc. Biopoly 41: 569–590, 1997.

Solution Structure of a Retro-inverso Peptide Analogue Mimicking the Foot-and-Mouth Disease Virus Major Antigenic Site

“…However, in the case of the retro-inverso peptide, the intensity of the Cotton effect at 222 nm was stronger ([⌰] ϭ ϩ6.20 ϫ 10 3 versus Ϫ4.49 ϫ 10 3 calculated for the L-peptide). This result is in good agreement with previous NMR investigations performed in TFE-d 2 on a related antigenic peptide (variant SL), which revealed that the helical region present in the C-terminal half (with respect to the parent sequence) of both peptides is more defined in the retro-inverso isomer (10,21). To further characterize the structural behavior of the retro-inverso isomer in solution, an H 2 O/TFE solvent titration was performed at room temperature.…”

“…To better understand the structural basis for antigenic mimicry between the L-peptide and its retro-inverso analogue, Carver et al (10) recently analyzed the L-and retro-inverso peptides 141-159 of the SL variant (with Ser and Leu residues at positions 148 and 153) by NMR spectroscopy and restrained molecular modelling. The NMR structures of the peptides were determined in trifluoroethanol-d 2 (TFE-d 2 ) at different temperatures.…”

“…Thus, a number of different structural features described for the L-and retroinverso peptide 141-159 are particularly significant, and this observation does not support the fact that the retro-inverso peptide displays similar or superior cross-reactive antigenic activity compared with the L-peptide with regard to anti-virus or anti-protein antibodies. As suggested by Carver et al (10), this discrepancy could be explained by assuming that the structures of the peptides in TFE do not correspond to those assumed by each peptide in aqueous solutions used to test their antigenic reactivity or in vivo when their immunogenic activity is investigated. In an attempt to rationalize our previous biological findings and explain why the retro-inverso analogue mimics the antigenic activity of the parent peptide, we decided to test whether anti-virus and anti-peptide antibodies effectively react with the peptides in TFE and determine the preferred conformers of the L-and retro-inverso peptides in aqueous solution.…”

The partial retro–inverso modification: A road traveled together

“…30 -32 inherently chiral structural elements, are roughly mirror images. 35 Both contain N-and C-terminal helical domains, right-handed in the RI and left-handed in the native sequence, and a ␥-turn around Gly 149 . In spite of the fact that the R 145 GD, which is involved in antibody recognition, has a different backbone conformation from that of the retro-inversed triad, they both adopt quasi-planar structures displaying very similar topologies.…”

“…Both the inherent flexibility around R 145 and the almost planarity of the recognition sequence explain the similarity in antigenic activity of the native peptide and its RI isomer. 35 In another study Guichard and coworkers reported the preparation of a series of PMRI analogs of the influenza matrix peptide 58 -66 [M(58 -66)] known to be a human leukocyte antigen (HLA)-A2-restricted epitope that binds preferentially nonapeptides with Leu, Met, or Ile in position P2 and Val, Leu, or Ile in position P9. 36 PMRI pseudopeptide [Gly 58 ⌿ (NH-CO)Leu 59 ]M(58 -66) was able to stabilize HLA-A2 at a concentration of 10 nM and was found to be more effective than the wild-type sequence in stimulating CD8 ϩ CTL to secrete interferon-␥ (INF-␥) and synthesize tumor necrosis factor (TNF)-␣ mRNA, cytokines involved in antiviral and antitumor responses.…”