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Antigenicity modulation upon peptide cyclization: application to the GH loop of foot-and-mouth disease virus strain
1Department of Organic Chemistry, University of Barcelona, Martí i Franquès 1, E-08028, Barcelona, Spain.
Abstract:
Foot-and-mouth disease virus (FMDV) isolate C(1)-Barcelona (or C-S30) includes four replacements within its immunodominant site (GH loop, residues 136-150 of capsid protein VP1, YTTSTRGDLAHVTAT), relative to reference strain C-S8c1 (YTASARGDLAHLTTT). Although one of the mutations in C-S30 (147Leu-->Val) is known to be detrimental for antibody recognition, reactivity of this isolate with the neutralizing monoclonal antibody (mAb) 4C4, raised against FMDV C1-Brescia (GH loop: YTASTRGDLAHLTAT), was indistinguishable from those of strains C-S8c1 or C1-Brescia. A structural interpretation for these somewhat striking findings is available, based on the observation that 15-residue peptides reproducing the C-S30 and C-S8c1 GH loops adopt very similar, quasi-circular, conformations in crystal complexes with 4C4. Nevertheless, surface plasmon resonance (SPR) kinetic analyses of the interactions between these peptides and three anti-GH loop mAbs have now revealed that the linear C-S30 peptides were less antigenic in solution than their C-S8c1 and C1-Brescia counterparts. We have, therefore, tried to modulate peptide antigenicity in solution by cyclization. Functional SPR and structural two dimensional proton nuclear magnetic resonance (2D-1H NMR) studies of both linear and cyclic peptide antigens are discussed here. Conformation seems to have an important role in peptide antigenicity, even when continuous (i.e. linear) antigenic sites are involved.
Insights
Foot-and-mouth disease virus (FMDV) mutations in the GH loop impact peptide antigenicity. Cyclization can modulate antigenicity, suggesting conformation is key for continuous antigenic sites.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- Foot-and-mouth disease virus (FMDV) isolate C(1)-Barcelona (C-S30) exhibits four amino acid substitutions in its immunodominant GH loop compared to reference strain C-S8c1.
- One mutation (147Leu-->Val) in C-S30 is known to impair antibody recognition, yet this isolate showed similar reactivity with a specific neutralizing monoclonal antibody (mAb) 4C4 as reference strains.
Purpose of the Study:
- To investigate the structural basis for the unexpected antibody reactivity of FMDV isolate C-S30.
- To evaluate the impact of linear versus cyclic peptide conformations on antigenicity using surface plasmon resonance (SPR) and 2D-1H NMR.
Main Methods:
- Comparative analysis of FMDV GH loop sequences.
- Structural studies using X-ray crystallography of peptide-mAb complexes.
- Kinetic analysis of peptide-mAb interactions via surface plasmon resonance (SPR).
- Conformational analysis using 2D proton nuclear magnetic resonance (2D-1H NMR).
Main Results:
- Fifteen-residue peptides mimicking the GH loops of C-S30 and C-S8c1 adopted similar quasi-circular conformations in complexes with mAb 4C4.
- SPR analysis revealed that linear C-S30 peptides were less antigenic in solution than C-S8c1 and C1-Brescia peptides.
- Cyclization of peptides was explored as a method to modulate antigenicity in solution.
Conclusions:
- Peptide conformation plays a significant role in antigenicity, even for continuous antigenic sites.
- Structural similarities in peptide-mAb complexes do not fully explain observed differences in solution-phase antigenicity.
- Modulating peptide conformation, potentially through cyclization, can influence antigenicity in solution.
