Synthesis and evaluation of redox-sensitive gonadotropin-releasing hormone receptor-targeting peptide conjugates

被引:4
作者
Dai, Yuxuan [1 ]
Yue, Na [1 ]
Liu, Chunxia [1 ]
Cai, Xingguang [1 ]
Su, Xin [1 ]
Bi, Xinzhou [1 ]
Li, Qifei [1 ]
Li, Chengye [1 ]
Huang, Wenlong [1 ,2 ]
Qian, Hai [1 ,2 ]
机构
[1] China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China
[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
Lytic peptides; Redox-sensitive; Membranolytic; Apoptosis; CANCER; PRODRUG; RICH; ACTIVATION; MECHANISMS; RESISTANCE; ARGININE; THERAPY; LYSINE;
D O I
10.1016/j.bioorg.2019.102945
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lytic peptides have been demonstrated to exhibit obvious advantages in cancer therapy with binding ability toward tumor cells via electrostatic attractions, which are lack of active targeting and aggregation to tumor tissue. In the present study, five conjugated lytic peptides were redesigned and constructed to target gonadotropin releasing hormone receptors (GnRHr), meanwhile, the disulfide bridge was introduced to achieve redox sensitive delivery based on the experience from the preliminary work of lytic peptides P3 and P7. YX-1, was considered to be the most promising for in-depth study. YX-1 possessed high potency (IC50 = 3.16 +/- 0.3 mu M), low hemolytic effect, and cell membrane permeability in human A2780 ovarian cancer cells. Moreover, YX-1 had prominent pro-apoptotic activity by activating the mitochondria-cytochrome c-caspase apoptotic pathway. The study yielded the conjugate YX-1 with superior properties for antineoplastic activity, which makes it a promising potential candidate for targeting cancer therapy.
引用
收藏
页数:9
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共 36 条
  • [1] Analysis of the effects of polyphenols on human spermatozoa reveals unexpected impacts on mitochondrial membrane potential, oxidative stress and DNA integrity; implications for assisted reproductive technology
    Aitken, R. J.
    Muscio, L.
    Whiting, S.
    Connaughton, H. S.
    Fraser, B. A.
    Nixon, B.
    Smith, N. D.
    De Iuliis, G. N.
    [J]. BIOCHEMICAL PHARMACOLOGY, 2016, 121 : 78 - 96
  • [2] [Anonymous], ACTA BIOMATER
  • [3] [Anonymous], ACS NANO
  • [4] [Anonymous], MOL PHARM
  • [5] [Anonymous], CANC STAT REV 1973 1
  • [6] [Anonymous], 2014, PLOS ONE, DOI DOI e100727.doi:10.1371/journal.pone.0100727
  • [7] [Anonymous], TEACHING TEACHER ED
  • [8] Structural Dissection of Crotalicidin, a Rattlesnake Venom Cathelicidin, Retrieves a Fragment with Antimicrobial and Antitumor Activity
    Borges Falcao, Claudio
    Perez-Peinado, Clara
    de la Torre, Beatriz G.
    Mayol, Xavier
    Zamora-Carreras, Hector
    Angeles Jimenez, M.
    Radis-Baptista, Gandhi
    Andreu, David
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (21) : 8553 - 8563
  • [9] Cationic Host Defence Peptides: Multifaceted Role in Immune Modulation and Inflammation
    Choi, Ka-Yee
    Chow, Leola N. Y.
    Mookherjee, Neeloffer
    [J]. JOURNAL OF INNATE IMMUNITY, 2012, 4 (04) : 361 - 370
  • [10] Novel Antimicrobial Peptides with High Anticancer Activity and Selectivity
    Chu, Hung-Lun
    Yip, Bak-Sau
    Chen, Kuan-Hao
    Yu, Hui-Yuan
    Chih, Ya-Han
    Cheng, Hsi-Tsung
    Chou, Yu-Ting
    Cheng, Jya-Wei
    [J]. PLOS ONE, 2015, 10 (05):