MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Budapest 112, P.O. Box 32, H-1518, Hungary.
Cancer Research Laboratory, Department of Pharmaceutical Sciences, University of Nottingham, Nottingham, NG7 2RD, United Kingdom.
Arch Biochem Biophys. 2019 Mar 30;664:127-133. doi: 10.1016/j.abb.2019.02.003. Epub 2019 Feb 8.
In order to establish structure-function relationship for the design of a new group of oligopeptide antigen-macromolecule conjugate, multiple copies of mucin-1 B-cell epitope peptide, APDTRPAPG were conjugated with branched chain polymeric polypeptides possessing poly[L-Lys] backbone. By the synthesis, radiolabeling (I) and in vivo treatment of BALB/c mice with epitope conjugates containing XK/XAK type carrier, where X = Glu (EK or EAK) or Leu (LAK), the influence of the polypeptide structure on the blood clearance profile and on tissue distribution profile concerning the epitope delivery to relevant organs (e.g. immunocompetent or involved in excretion) were investigated. We observed significant differences in the blood clearance profiles for the conjugates, the respective polypeptide carriers and free epitope peptide. All conjugates, regardless of their charge properties exhibited longer presence in the circulation than the free oligopeptide. Tissue distribution data also showed that the structural properties (e.g. amino acid composition, charge) of the carrier polypeptide have marked influence on the tissue accumulation of the epitope peptide conjugates. In contrast to conjugates with linear (K) or branched chain (LAK) polycationic polymers exhibiting rapid blood clearance and high spleen/liver uptake, amphoteric epitope peptide conjugates with different branches, but similar charge properties (EK or EAK) had extended blood survival and generally lower tissue accumulation. The results on this systematic investigation suggest that further studies on the immune response induced by these epitope conjugates would be needed to provide correlation between biodistribution properties (presence in the blood, level of tissue accumulation) and the capacity of these conjugates to elicit antibody production.
为了建立新的一组寡肽抗原-大分子缀合物的结构-功能关系，将多个粘蛋白-1 B 细胞表位肽 APDTRPAPG 与具有支链聚合物多肽缀合，该多肽具有聚[L-赖氨酸]主链。通过合成、放射性标记（I）和用含有 XK/XAK 型载体的表位缀合物（其中 X = Glu（EK 或 EAK）或 Leu（LAK））处理 BALB/c 小鼠，研究了多肽结构对表位递送至相关器官（例如免疫活性或参与排泄）的血液清除谱和组织分布谱的影响。我们观察到缀合物、各自的多肽载体和游离表位肽的血液清除谱存在显著差异。所有缀合物，无论其电荷性质如何，在循环中的存在时间均长于游离寡肽。组织分布数据还表明，载体多肽的结构特性（例如氨基酸组成、电荷）对表位肽缀合物的组织积累有明显影响。与具有线性（K）或支链（LAK）聚阳离子聚合物的缀合物（具有快速的血液清除和高的脾/肝摄取）相反，具有不同支链但具有相似电荷性质（EK 或 EAK）的两性表位肽缀合物具有延长的血液存活时间，并且通常较低的组织积累。这项系统研究的结果表明，需要进一步研究这些表位缀合物诱导的免疫反应，以提供生物分布特性（在血液中的存在、组织积累水平）与这些缀合物引发抗体产生能力之间的相关性。
