title: Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors.
abstract: Hepsin, a type II transmembrane serine protease, is an attractive protein as a potential therapeutic and diagnostic biomarker for prostate cancer because it is highly up-regulated in prostate cancer and promotes both progression and metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22nM and 3nM, respectively. The present work suggests that LR-containing dipeptide molecules could be useful as lead compounds for the development of novel hepsin inhibitors.
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Hongmok
authors.initials: H
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: YunHye
authors.initials: Y
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Kieung
authors.initials: K
authors.lastname: Park
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea.
authors.forename: Soo An
authors.initials: SA
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea. Electronic address: shson@korea.ac.kr.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Son
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-ro, Jochiwon-eup, Sejong 339-700, South Korea. Electronic address: yjbyun1@korea.ac.kr.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D004151:Dipeptides; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; C000613567:acetyl-leucyl-arginyl-ketobenzothiazole; C000613566:acetyl-leucyl-arginyl-ketothiazole; C078789:leucylarginine; D012697:Serine Endopeptidases; C055645:hepsin; C485595:matriptase
keywords: Dipeptides; Hepsin; Prostate cancer; Serine protease