Conformational restriction of peptidyl immunogens with covalent replacements for the hydrogen bond.
A new strategy for designing synthetic vaccines is presented. In this approach synthetic peptides are conformationally restricted by replacing putative hydrogen bonds with covalent mimics. The chemistry for substituting a hydrazone-ethane link (N-N = CH-CH2-CH2) for an (i + 4)----i hydrogen bond in a pentapeptide with alpha-helical potential is reported. Chemically shaping peptides to mimic the three-dimensional surfaces of proteins may enhance their immunogenicity. To test this strategy, a potential synthetic vaccine for malaria, Cys-(Asn-Pro-Asn-Ala)3-NH2, was conformationally restricted by replacing putative hydrogen bonds between asparagine side chains with a covalent replacement, an ethylene bridge, to give first generation chemically shaped immunogens. Antibodies to one of the shaped malarial peptides show a strong reaction with living Plasmodium falciparum sporozoites, a form of malaria which infects hundreds of millions of people yearly.
Satterthwait
A C
AC
Research Institute of Scripps Clinic, La Jolla, CA.
Arrhenius
T
T
Hagopian
R A
RA
Zavala
F
F
Nussenzweig
V
V
Lerner
R A
RA
D000818:Animals; D000941:Antigens / Q000276:immunology*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology; D011487:Protein Conformation; D014614:Vaccines, Synthetic / Q000276:immunology* / Q000302:isolation & purification
D000941:Antigens; D009842:Oligopeptides; D014614:Vaccines, Synthetic