Hudecz F, Clegg J A, Kajtár J, Embleton M J, Szekerke M, Baldwin R W
Research Group for Peptide Chemistry, Hungarian Academy of Science, Budapest.
Bioconjug Chem. 1992 Jan-Feb;3(1):49-57. doi: 10.1021/bc00013a008.
Daunomycin has been attached to various structurally related synthetic branched polypeptides with a polylysine backbone, using its acid-labile cis-aconityl derivative (cAD). Due to the importance of the side-chain structure in alpha-helix formation and immunological and pharmacological properties of branched polypeptides, we have investigated the conformation, biodistribution, and in vitro cytotoxicity of cAD-carrier conjugates with polypeptides containing amino acid residues of different identity and/or configuration at the side-chain end (XAK type) or at the position next to the polylysine backbone (AXK type), where X = Leu, D-Leu, Pro, Glu, or D-Glu. According to CD studies, polycationic conjugates with hydrophobic Leu in the side chains could assume a highly ordered conformation, while amphoteric conjugates containing Glu proved to be unordered in PBS. The reduction of in vitro cytotoxic activity of cAD by conjugation to carriers and the biodistribution profile of the conjugates were found to be dependent predominantly on the charge properties and on the side-chain sequence of the carrier polypeptide. It was demonstrated that by proper combination of structural elements of the carrier molecule, it is feasible to construct a cAD-branched polypeptide conjugate with significantly prolonged blood survival and with no reduction in in vitro cytotoxicity of the drug.
柔红霉素已通过其酸不稳定的顺乌头酰衍生物（cAD）连接到各种具有聚赖氨酸主链的结构相关合成支链多肽上。由于侧链结构在α-螺旋形成以及支链多肽的免疫学和药理学特性中的重要性，我们研究了cAD-载体缀合物与在侧链末端（XAK型）或聚赖氨酸主链旁边的位置（AXK型）含有不同身份和/或构型氨基酸残基的多肽的构象、生物分布和体外细胞毒性，其中X = Leu、D-Leu、Pro、Glu或D-Glu。根据圆二色性研究，侧链中含有疏水Leu的聚阳离子缀合物可以呈现高度有序的构象，而含有Glu的两性缀合物在磷酸盐缓冲盐溶液中被证明是无序的。发现通过与载体缀合降低cAD的体外细胞毒性活性以及缀合物的生物分布概况主要取决于载体多肽的电荷性质和侧链序列。结果表明，通过适当组合载体分子的结构元件，构建一种具有显著延长血液存活时间且药物体外细胞毒性不降低的cAD-支链多肽缀合物是可行的。
