Wieczorek Sebastian, Remmler Dario, Masini Tiziana, Kochovski Zdravko, Hirsch Anna K H, Börner Hans G
Department of Chemistry, Laboratory for Organic Synthesis of Functional Systems, Humboldt-Universität zu Berlin , Brook-Taylor-Str. 2, 12489 Berlin, Germany.
Stratingh Institute for Chemistry, University of Groningen , Nijenborgh 7, NL-9747 AG Groningen, The Netherlands.
Bioconjug Chem. 2017 Mar 15;28(3):760-767. doi: 10.1021/acs.bioconjchem.6b00549. Epub 2017 Jan 13.
Tailor-made drug solubilizers are studied based on peptide-poly(ethylene glycol) conjugates, which exhibit peptide segments constituting binding motifs for the small-molecule drugs of interest to render them water-soluble. Suitable 7mer peptides are selected via combinatorial means by screening large one-bead-one-compound (OBOC) peptide libraries. The capability of the screening method to read out structural detail of the drugs is investigated by comparing three related photosensitizers (Chlorin E6 (Ce6), Pheophorbide A (Pba) and meta-tetra(hydroxyphenyl)chlorin (m-THPC), which are applicable for photodynamic cancer therapy. The screening procedure delivers de novo solubilizers that show the best solubilization efficiency for the drug the screening is performed with. While molecular recognition events between peptide and drug are not expected to be found, significant binding capacity differences of, e.g., the Ce6-solubilizer for Pba are suggesting selectivity in drug binding, even among structurally closely related drugs. Cyro-Electron microscopy revealed the formation of colloidal aggregates between drug moieties and peptide conjugates. Insights into relevant amino acids in the identified peptide sequences are gained by studying capacities of systematic point mutations (alanine scans), enabling understanding of drug-binding motifs. These reveal the importance of sequence positioning of appropriate H-bonding between polar functional groups of the peptide and the drugs, which agrees well with computational binding studies performed on drug/peptide model complexes.
基于肽-聚乙二醇缀合物研究了定制的药物增溶剂，该缀合物展示了构成目标小分子药物结合基序的肽段，以使这些药物具有水溶性。通过筛选大型单珠单化合物（OBOC）肽库，采用组合方法选择合适的7聚体肽。通过比较三种适用于光动力癌症治疗的相关光敏剂（二氢卟吩e6（Ce6）、脱镁叶绿酸a（Pba）和间四（羟苯基）氯卟啉（m-THPC）），研究了筛选方法读出药物结构细节的能力。筛选过程产生了对所筛选药物显示出最佳增溶效率的全新增溶剂。虽然预计在肽和药物之间不会发现分子识别事件，但例如Ce6增溶剂对Pba的显著结合能力差异表明，即使在结构密切相关的药物中，药物结合也具有选择性。冷冻电子显微镜揭示了药物部分与肽缀合物之间形成了胶体聚集体。通过研究系统点突变（丙氨酸扫描）的能力，深入了解了已鉴定肽序列中的相关氨基酸，从而能够理解药物结合基序。这些结果揭示了肽的极性官能团与药物之间适当氢键序列定位的重要性，这与对药物/肽模型复合物进行的计算结合研究结果非常吻合。
