title: Pyrrole-Based Macrocyclic Small-Molecule Inhibitors That Target Oocyte Maturation.
abstract: Polo-like kinase 1 (PLK1) plays crucial roles in various stages of oocyte maturation. Recently, we reported that the peptidomimetic compound AB103-8, which targets the polo box domain (PBD) of PLK1, affects oocyte meiotic maturation and the resumption of meiosis. However, to overcome the drawbacks of peptidic compounds, we designed and synthesized a series of pyrrole-based small-molecule inhibitors and tested them for their effects on the rates of porcine oocyte maturation. Among them, the macrocyclic compound (E/Z)-3-(2,16-dioxo-19-(4-phenylbutyl)-3,19-diazabicyclo[15.2.1]icosa-1(20),6,17-trien-3-yl)propyl dihydrogen phosphate (4) showed the highest inhibitory activity with enhanced inhibition against embryonic blastocyst formation. Furthermore, the addition of this compound to culture media efficiently blocked the maturation of porcine and mouse oocytes, indicating its ability to penetrate the zona pellucida and cell membrane. We investigated mouse oocytes treated with compound 4, and the resulting impairment of spindle formation confirmed PLK1 inhibition. Finally, molecular modeling studies with PLK1 PBD also confirmed the presence of significant interactions between compound 4 and PLK1 PBD binding pocket residues, including those in the phosphate, tyrosine-rich, and pyrrolidine binding pockets. Collectively, these results suggest that the macrocyclic compound 4 may serve as a promising template for the development of novel contraceptive agents.
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: Pethaiah
authors.initials: P
authors.lastname: Gunasekaran
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: So-Rim
authors.initials: SR
authors.lastname: Lee
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Jeong
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: Jeong-Woo
authors.initials: JW
authors.lastname: Kwon
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takei
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Asahina
authors.affiliation: Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.
authors.forename: Geul
authors.initials: G
authors.lastname: Bang
authors.affiliation: Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.
authors.forename: Seongnyeon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.
authors.forename: Mija
authors.initials: M
authors.lastname: Ahn
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.|Department of Bio-analytical Science, University of Science & Technology, Daejeon, 34113, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Ryu
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.
authors.forename: Hak Nam
authors.initials: HN
authors.lastname: Kim
authors.affiliation: Pharos I&BT Co. Ltd., Gyeonggi-do, 14059, Republic of Korea.
authors.forename: Ki-Yub
authors.initials: KY
authors.lastname: Nam
authors.affiliation: Department of Medical Science, Graduate School and Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea.
authors.forename: Song Yub
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hojo
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: Suk
authors.initials: S
authors.lastname: Namgoong
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: Nam-Hyung
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.|Department of Bio-analytical Science, University of Science & Technology, Daejeon, 34113, Republic of Korea.
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Bang
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002463:Cell Membrane Permeability; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects*; D010755:Organophosphates / Q000138:chemical synthesis / Q000494:pharmacology; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology; D013552:Swine; D015044:Zona Pellucida / Q000187:drug effects / Q000502:physiology; D000097869:Polo-Like Kinase 1
chemical_list: D053961:Azabicyclo Compounds; D018797:Cell Cycle Proteins; D047028:Macrocyclic Compounds; D009842:Oligopeptides; D010755:Organophosphates; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D000097869:Polo-Like Kinase 1; C000622774:3-(2,16-dioxo-19-(4-phenylbutyl)-3,19-diazabicyclo(15.2.1)icosa-1(20),6,17-trien-3-yl)propyl dihydrogen phosphate; C000622775:AB103-8
keywords: contraceptive agents; inhibitors; macrocycles; oocyte maturation; polo-like kinase 1