Argyrin B, a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i

被引:8
作者
Allardyce, Duncan J. [1 ]
Bell, Celia M. [1 ]
Loizidou, Eriketi Z. [1 ]
机构
[1] Middlesex Univ, Fac Sci & Technol, Dept Nat Sci, London NW4 4BT, England
关键词
argyrin B; docking; immunoproteasome; non-competitive binding; selective inhibitors; UBIQUITIN-PROTEASOME SYSTEM; BACTERIAL PROTEIN-SYNTHESIS; 20S PROTEASOME; BIOLOGICAL EVALUATION; SELECTIVE INHIBITOR; CRYSTAL-STRUCTURE; ACTIVE-SITES; PEPTIDES; SUBTYPES; COMPLEX;
D O I
10.1111/cbdd.13539
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
Inhibitors of the proteasome have found broad therapeutic applications; however, they show severe toxicity due to the abundance of proteasomes in healthy cells. In contrast, inhibitors of the immunoproteasome, which is upregulated during disease states, are less toxic and have increased therapeutic potential including against autoimmune disorders. In this project, we report argyrin B, a natural product cyclic peptide to be a reversible, non-competitive inhibitor of the immunoproteasome. Argyrin B showed selective inhibition of the beta 5i and beta 1i sites of the immunoproteasome over the beta 5c and beta 1c sites of the constitutive proteasome with nearly 20-fold selective inhibition of beta 1i over the homologous beta 1c. Molecular modelling attributes the beta 1i over beta 1c selectivity to the small hydrophobic S1 pocket of beta 1i and beta 5i over beta 5c to site-specific amino acid variations that enable additional bonding interactions and stabilization of the binding conformation. These findings facilitate the design of immunoproteasome selective and reversible inhibitors that may have a greater therapeutic potential and lower toxicity.
引用
收藏
页码:1556 / 1567
页数:12
相关论文
共 63 条
  • [51] Ixazomib: an oral proteasome inhibitor for the treatment of multiplemyeloma
    Shah, Neil
    Biran, Noa
    Vesole, David H.
    [J]. EXPERT OPINION ON ORPHAN DRUGS, 2016, 4 (01): : 105 - 113
  • [52] PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo
    Singh, Ajita V.
    Bandi, Madhavi
    Aujay, Monette A.
    Kirk, Christopher J.
    Hark, David E.
    Raje, Noopur
    Chauhan, Dharminder
    Anderson, Kenneth C.
    [J]. BRITISH JOURNAL OF HAEMATOLOGY, 2011, 152 (02) : 155 - 163
  • [53] Elucidation of the Structure and Intermolecular Interactions of a Reversible Cyclic-Peptide Inhibitor of the Proteasome by NMR Spectroscopy and Molecular Modeling
    Stauch, Benjamin
    Simon, Bernd
    Basile, Teodora
    Schneider, Gisbert
    Malek, Nisar P.
    Kalesse, Markus
    Carlomagno, Teresa
    [J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2010, 49 (23) : 3934 - 3938
  • [54] The role of the ubiquitin proteasome system in lymphoma
    Suh, K. Stephen
    Tanaka, Takemi
    Sarojini, Sreeja
    Nightingale, Ginah
    Gharbaran, Rajendra
    Pecora, Andrew
    Goy, Andre
    [J]. CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2013, 87 (03) : 306 - 322
  • [55] Synthesis, Bioactivity, Docking and Molecular Dynamics Studies of Furan-Based Peptides as 20S Proteasome Inhibitors
    Sun, Qi
    Xu, Bo
    Niu, Yan
    Xu, Fengrong
    Liang, Lei
    Wang, Chao
    Yu, Jiapei
    Yan, Gang
    Wang, Wei
    Jin, Hongwei
    Xu, Ping
    [J]. CHEMMEDCHEM, 2015, 10 (03) : 498 - 510
  • [56] Proteasome inhibitors Commentary
    Teicher, Beverly A.
    Tomaszewski, Joseph E.
    [J]. BIOCHEMICAL PHARMACOLOGY, 2015, 96 (01) : 1 - 9
  • [57] Proteasome Subtypes and Regulators in the Processing of Antigenic Peptides Presented by Class I Molecules of the Major Histocompatibility Complex
    Vigneron, Nathalie
    Van den Eynde, Benoit J.
    [J]. BIOMOLECULES, 2014, 4 (04): : 994 - 1025
  • [58] Inhibition of the Proteasome β2 Site Sensitizes Triple-Negative Breast Cancer Cells to β5 Inhibitors and Suppresses Nrf1 Activation
    Weyburne, Emily S.
    Wilkins, Owen M.
    Sha, Zhe
    Williams, David A.
    Pletnev, Alexandre A.
    de Bruin, Gerjan
    Overkleeft, Hermann S.
    Goldberg, Alfred L.
    Cole, Michael D.
    Kisselev, Alexei F.
    [J]. CELL CHEMICAL BIOLOGY, 2017, 24 (02): : 218 - 230
  • [59] Proteasome inhibition: A new therapeutic strategy to cancer treatment
    Wu, William Ka Kei
    Cho, Chi Hin
    Lee, Chung Wa
    Wu, Kaichun
    Fan, Daiming
    Yu, Jun
    Sung, Joseph Jao Yiu
    [J]. CANCER LETTERS, 2010, 293 (01) : 15 - 22
  • [60] Immunoproteasomes: Regulating the regulator
    Yewdell, JW
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (26) : 9089 - 9090