title: Enhanced cellular uptake of a TAT-conjugated peptide inhibitor targeting the polo-box domain of polo-like kinase 1.
abstract: In the last decade, drug delivery systems using biologically active molecules for cellular uptake of therapeutic targets have been studied for application and testing in clinical trials. For instance, the transactivator of transcription (TAT) peptide, or cell-penetrating peptide, was shown to deliver a variety of cargoes, including proteins, peptides, and nucleic acids. Polo-like kinase 1 (Plk1) plays key roles in the regulation of cell cycle events (e.g., mitotic progression). Plk1 was also shown to be activated and highly expressed in proliferating cells such as tumor cells. Amongst these phosphopeptides, Pro-Leu-His-Ser-p-Thr (PLHSpT), which is the minimal sequence for polo-box domain (PBD) binding, was shown to have an inhibitory effect and to induce apoptotic cell death. However, the phosphopeptide showed low cell membrane penetration. Thus, in our study, we synthesized Plk1 inhibitor TAT-PLHSpT to improve agent internalization into cells. TAT-PLHSpT was shown to internalize into the nucleus. The conjugation of TAT with PLHSpT inhibited cancer cell growth and survival. Moreover, it showed an increase in cellular uptake and inhibition of Plk1 kinase activity. Further studies are needed for biological evaluation of the new peptide in tumor-bearing animal models (in vivo). Our results prove that TAT-PLHSpT is a good candidate for specific PBD binding of Plk1 as a therapeutic agent for humans.
authors.affiliation: Magnetic Resonance Research Center, Korea Basic Science Institute, 804-1 Ochang, Cheongju, Chungbuk, 363-883, Republic of Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Kim
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Chae
authors.forename: Chulhyun
authors.initials: C
authors.lastname: Lee
authors.forename: Min Su
authors.initials: MS
authors.lastname: Yim
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Bang
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Ryu
mesh_terms: D000165:Acridine Orange / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D015696:Gene Products, tat / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009369:Neoplasms / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000097869:Polo-Like Kinase 1
chemical_list: D000165:Acridine Orange; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004337:Drug Carriers; D015696:Gene Products, tat; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1