Paasonen Lauri, Sharma Shweta, Braun Gary B, Kotamraju Venkata Ramana, Chung Thomas D Y, She Zhi-Gang, Sugahara Kazuki N, Yliperttula Marjo, Wu Bainan, Pellecchia Maurizio, Ruoslahti Erkki, Teesalu Tambet
University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, Viikinkaari 5E, Helsinki, 00014, Finland.
Sanford Burnham Prebys Medical Discovery Institute, Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, CA, 93027, USA.
Chembiochem. 2016 Apr 1;17(7):570-5. doi: 10.1002/cbic.201500564. Epub 2016 Feb 19.
Cell surface p32, the target of LyP-1 homing peptide, is upregulated in tumors and atherosclerotic plaques and has been widely used as a receptor for systemic delivery of payloads. Here, we identified an improved LyP-1-mimicking peptide (TT1, CKRGARSTC). We used this peptide in a fluorescence polarization-based high-throughput screening of a 50,000-compound chemical library and identified a panel of compounds that bind p32 with low micromolar affinity. Among the hits identified in the screen, two compounds were shown to specifically bind to p32 in multiple assays. One of these compounds was chosen for an in vivo study. Nanoparticles surface-functionalized with this compound specifically adhered to surfaces coated with recombinant p32 and, when injected intravenously, homed to p32-expressing breast tumors in mice. This compound provides a lead for the development of p32-targeted affinity ligands that circumvent some of the limitations of peptide-based probes in guided drug delivery.
细胞表面p32是LyP-1归巢肽的靶点，在肿瘤和动脉粥样硬化斑块中上调，已被广泛用作全身递送有效载荷的受体。在此，我们鉴定了一种改进的模拟LyP-1的肽（TT1，CKRGARSTC）。我们将此肽用于基于荧光偏振的50000化合物化学文库的高通量筛选，并鉴定了一组以低微摩尔亲和力结合p32的化合物。在筛选出的命中化合物中，有两种化合物在多种测定中显示出特异性结合p32。其中一种化合物被选用于体内研究。用该化合物进行表面功能化的纳米颗粒特异性粘附于涂有重组p32的表面，静脉注射后，归巢至小鼠中表达p32的乳腺肿瘤。该化合物为开发靶向p32的亲和配体提供了线索，这些配体可规避基于肽的探针在导向药物递送中的一些局限性。
