Exploiting conformationally constrained peptidomimetics and an efficient human-compatible delivery system in synthetic vaccine design

Peptide and protein mimetics are potentially of great value in synthetic va ccine design. The mimetics should function by the immune system to produce antibodies that recognize the intact parasite. Also the mimetics should be presented to the immune system in a way that leads to efficient antibody pr oduction. Here we investigate the application of cyclic peptidomimetics pre sented on immunopotentiating reconstituted influenza virosomes (IRIVs), a f orm of antigen delivery that is licensed already for human clinical use, in synthetic vaccine design. We focus-on the central (NPNA), repeat region of the circumsporozoite (CS) protein of the malaria parasite Plasmodium falci parum as a model system. Cyclic peptidomimetics of the AMA repeats were inc orporated into both an IRIV and (for comparison) a multiple-antigen peptide (MAP). Both IRIV and MAP delivery forms induced mimetic-specific humoral i mmune responses in mice, but only with the mimetic-IRIV preparations did a significant fraction of the elicited antibodies cross-react with sporozoite s. The results demonstrate that IRIVs are a delivery system suitable for th e efficient induction of antibody responses against conformational epitopes by use of cyclic template-bound peptidomimetics. Combined with combinatori al chemistry, this approach may have great potential for the rapid optimiza tion of molecularly defined synthetic vaccine candidates against a wide var iety of infectious agents.