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 vaccine design. The mimetics should function by stimulating 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 production. Here we investigate the application of cyclic peptidomimetics presented on immunopotentiating reconstituted influenza virosomes (IRIVs), a form of antigen delivery that is licensed already for human clinical use, in synthetic vaccine design. We focus on the central (NPNA)n repeat region of the circumsporozoite (CS) protein of the malaria parasite Plasmodium falciparum as a model system. Cyclic peptidomimetics of the NPNA repeats were incorporated into both an IRIV and (for comparison) a multiple‐antigen peptide (MAP). Both IRIV and MAP delivery forms induced mimetic‐specific humoral immune responses in mice, but only with the mimetic‐IRIV preparations did a significant fraction of the elicited antibodies cross‐react with sporozoites. The results demonstrate that IRIVs are a delivery system suitable for the efficient induction of antibody responses against conformational epitopes by use of cyclic template‐bound peptidomimetics. Combined with combinatorial chemistry, this approach may have great potential for the rapid optimization of molecularly defined synthetic vaccine candidates against a wide variety of infectious agents. Designing and delivering: The design of peptidomimetics for use as synthetic vaccines is of increasing importance in medicinal chemistry. The mimetic should efficiently elicit antibodies that cross‐react with infectious agents. Constrained peptidomimetics of the Asn‐Pro‐Asn‐Ala‐Asn motif from the major surface protein of Plasmodium falciparum sporozoites, when presented to the immune system on virus‐like particles, are shown to elicit an efficient parasite cross‐reactive antibody response. This delivery system has been licensed for human use, which opens a direct route for clinical testing.