Synthesis, Conformational Properties, and Immunogenicity of a Cyclic Template-Bound Peptide Mimetic Containing an NPNA Motif from the Circumsporozoite Protein of Plasmodium falciparum
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- 作者：Christian Bisang ; Luyong Jiang ; Ernst Freund ; Fabienne Emery ; Christian Bauch ; Hugues Matile ; Gerd Pluschke ; and John A. Robinson
- 刊名：Journal of the American Chemical Society
- 出版年：1998
- 出版时间：August 5, 1998
- 年：1998
- 卷：120
- 期：30
- 页码：7439 - 7449
- 全文大小：296K
- 年卷期：v.120,no.30(August 5, 1998)
- ISSN：1520-5126
文摘
The immunodominant central portion of the circumsporozoite (CS) surface protein of the malariaparasite Plasmodium falciparum contains a tetrapeptide motif, Asn-Pro-Asn-Ala (NPNA), tandemly repeatedalmost 40 times. The three-dimensional structure of the CS protein, including the central repeat region, ispresently unknown. We have investigated an approach to stabilize 
-turns in a single NPNA motif, by itsincorporation into a template-bound cyclic peptide comprising the sequence ANPNAA. The template wasdesigned to stabilize -turns in the peptide loop and to allow its conjugation to T-cell epitopes in a multiple-antigen-peptide. NMR studies and MD simulations with time-averaged NOE-derived upper distance restraintssupport the formation of a stable -I turn conformation in the NPNA motif of this template-bound antigen.Balb/c mice immunized with a multiple-antigen-peptide containing four copies of the template-bound loopconjugated to a single universal T-cell epitope produced antibodies that bound P. falciparum sporozoites inimmunofluorescence assays. These results provide further support for the immunological relevance of a type-I-turn conformation based on the NPNA cadence in the repeat region of the CS protein and illustrate the useof a novel template for the evaluation of conformationally constrained peptide immunogens.
-turns in a single NPNA motif, by itsincorporation into a template-bound cyclic peptide comprising the sequence ANPNAA. The template wasdesigned to stabilize -turns in the peptide loop and to allow its conjugation to T-cell epitopes in a multiple-antigen-peptide. NMR studies and MD simulations with time-averaged NOE-derived upper distance restraintssupport the formation of a stable -I turn conformation in the NPNA motif of this template-bound antigen.Balb/c mice immunized with a multiple-antigen-peptide containing four copies of the template-bound loopconjugated to a single universal T-cell epitope produced antibodies that bound P. falciparum sporozoites inimmunofluorescence assays. These results provide further support for the immunological relevance of a type-I-turn conformation based on the NPNA cadence in the repeat region of the CS protein and illustrate the useof a novel template for the evaluation of conformationally constrained peptide immunogens.