Satterthwait A C, Chiang L C, Arrhenius T, Cabezas E, Zavala F, Dyson H J, Wright P E, Lerner R A
Research Institute of Scripps Clinic, La Jolla, CA 92037.
Bull World Health Organ. 1990;68 Suppl(Suppl):17-25.
The effectiveness of synthetic vaccines is dependent upon the chance event that antibodies formed against largely disordered peptides can bind native protein surfaces which are often ordered. To improve on this situation, new methods are being developed for the conformational restriction of synthetic peptides. Cognate peptide sequences often form predictable secondary structures in proteins characterized by distinct hydrogen-bonding patterns. These weak hydrogen bonds have now been replaced with covalent mimics to conformationally restrict selected peptides to the Type 1 reverse turn and alpha helix. Potential uses for this chemistry are discussed in the context of malaria vaccines. The peptide component of a Plasmodium falciparum sporozoite vaccine, acetyl-(ASN-ALA-ASN-PRO)3-NH2 has been conformationally analysed using two-dimensional nuclear magnetic resonance spectroscopy. These studies are consistent with the formation of transiently ordered turnlike structures which provide a guide for the design and synthesis of a conformationally restricted synthetic vaccine. To assess the effects of conformational restriction and chemical modification on the sporozoite vaccine, ASN side-chains were linked around proline with ethylene bridges. Polyclonal antibodies to this shaped peptide show a strong cross-reaction with living sporozoites.
针对大多无序肽形成的抗体能够结合通常有序的天然蛋白质表面。为改善这种情况，人们正在开发新方法来对合成肽进行构象限制。同源肽序列在蛋白质中常常形成具有独特氢键模式特征的可预测二级结构。现在这些弱氢键已被共价模拟物取代，以便将选定的肽构象限制为1型反向转角和α螺旋。在疟疾疫苗的背景下讨论了这种化学方法的潜在用途。恶性疟原虫子孢子疫苗的肽组分乙酰基-(ASN-ALA-ASN-PRO)3-NH2已通过二维核磁共振光谱进行了构象分析。这些研究与瞬时有序的转角样结构的形成一致，这为构象受限的合成疫苗的设计和合成提供了指导。为评估构象限制和化学修饰对子孢子疫苗的影响，天冬酰胺侧链通过乙烯桥连接在脯氨酸周围。针对这种构象肽的多克隆抗体与活子孢子表现出强烈的交叉反应。
