A retro-inverso peptide corresponding to the GH loop of foot-and-mouth disease virus elicits high levels of long-lasting protective neutralizing antibodies

Abstract

Peptides corresponding to the immunodominant loop located at residues 135-158 on capsid protein VP1 of foot-and-mouth disease virus (FMDV) generally elicit high levels of anti-peptide and virus-neutralizing antibodies. In some instances, however, the level of neutralizing antibodies is low or even negligible, even though the level of anti-peptide antibodies is high. We have shown previously that the antigenic activity of peptide 141-159 of VP1 of a variant of serotype A can be mimicked by a retro-inverso (all-D retro or retroenantio) peptide analogue. This retro-inverso analogue induced greater and longer-lasting antibody titers than did the corresponding L-peptide. We now show that a single inoculation of the retro-inverso analogue elicits high levels of neutralizing antibodies that persist longer than those induced against the corresponding L-peptide and confer substantial protection in guinea pigs challenged with the cognate virus. In view of the high stability to proteases of retro-inverso peptide analogues and their enhanced immunogenicity, these results have practical relevance in designing potential peptide vaccines.

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

“…The enhanced immunogenic reactivities of retro-inverso analogues may result from their higher resistance to proteolysis in biological fluids (7). However, this property does not explain why in immunochemical assays, retro-inverso peptides are often better recognized than the parent peptide by anti-virus, anti-protein, or anti-peptide antibodies with equilibrium affinity constants which can be increased by 10 -100 in some instances (7)(8)(9).…”

“…CD and NMR studies were performed with peptides that contained no additional cysteine. The synthesis and purification of the peptides were described previously (6,7). The N terminus of the L-peptides was acetylated, whereas their C terminus was left as -COOH.…”

“…Most importantly, the retro-inverso analogues, also called retro all-D or retro-enantio peptides (4,5), induced greater and longer-lasting antibody titers than did the respective parent peptides (6). Moreover, we showed with the FP variant analogue (which contains Phe and Pro residues at positions 148 and 153, respectively) that a single inoculation of the retro-inverso peptide elicited high levels of neutralizing antibodies that persisted longer than those induced against the corresponding L-peptide and protected guinea pigs challenged with the cognate virus (7). The enhanced immunogenic reactivities of retro-inverso analogues may result from their higher resistance to proteolysis in biological fluids (7).…”

“…Moreover, we showed with the FP variant analogue (which contains Phe and Pro residues at positions 148 and 153, respectively) that a single inoculation of the retro-inverso peptide elicited high levels of neutralizing antibodies that persisted longer than those induced against the corresponding L-peptide and protected guinea pigs challenged with the cognate virus (7). The enhanced immunogenic reactivities of retro-inverso analogues may result from their higher resistance to proteolysis in biological fluids (7). However, this property does not explain why in immunochemical assays, retro-inverso peptides are often better recognized than the parent peptide by anti-virus, anti-protein, or anti-peptide antibodies with equilibrium affinity constants which can be increased by 10 -100 in some instances (7)(8)(9).…”

The partial retro–inverso modification: A road traveled together

“…Inoculation of guinea pigs with the RI peptide provided greater protection when challenged with the cognate virus. 33 Although the Arc-Gly-Asp (RGD) triad at positions 145-147 of the immunodominant loop is directly involved in the attachment to integrins ␣ V ␤ 3 and ␣ 5 ␤ 1 present on the susceptible cells, the amino acid sequences flanking the RGD triad are critical in the infectious process and in determining the specificity of the resultant antibodies. 34 Interestingly, the conformations of FMDV VP1(148 -159) variant A and its end-group modified RI peptide, which share FIGURE 7 Book cover from the 14th annual meeting on Modern Approaches to the Control of Infectious Diseases held in early September of 1996 at the Cold Spring Harbor Laboratory.…”