Suppr超能文献

新型小分子CCR5拮抗剂TAK-220在人CCR5上的结合位点分析

Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5.

作者信息

Nishikawa Masao, Takashima Katsunori, Nishi Toshiya, Furuta Rika A, Kanzaki Naoyuki, Yamamoto Yoshio, Fujisawa Jun-Ichi

机构信息

Department of Microbiology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.

出版信息

Antimicrob Agents Chemother. 2005 Nov;49(11):4708-15. doi: 10.1128/AAC.49.11.4708-4715.2005.

Abstract

G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.

摘要

G蛋白偶联受体CCR5是嗜巨噬细胞性1型人类免疫缺陷病毒(HIV-1)的主要共受体,目前正在研发各种小分子CCR5拮抗剂来治疗HIV-1感染。据报道,包括TAK-779在内的此类CCR5拮抗剂可与CCR5跨膜结构域(TM)1、2、3和7形成的假定结合口袋结合,这表明病毒进入过程中TM构象变化的重要性。在本报告中,我们使用人类CCR5及其替代突变体进行单轮感染试验,证明新型CCR5拮抗剂TAK-220与TAK-779在TM6中共有假定的相互作用氨基酸残基Asn252和Leu255,但还分别需要TM4和TM5中的不同残基Gly163和Ile198来发挥其抑制作用。我们认为,结合药物与CCR5之间相互作用的分子模型,TAK-220的抑制活性除了与先前假定的结合口袋中的氨基酸残基直接相互作用外,还可能涉及与TM4、TM5和TM6中的氨基酸残基直接相互作用。药物与CCR5分子其他区域可能的相互作用将有助于开发新型小分子CCR5拮抗剂。

相似文献

1
Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5.
Antimicrob Agents Chemother. 2005 Nov;49(11):4708-15. doi: 10.1128/AAC.49.11.4708-4715.2005.
2
Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists.
Mol Pharmacol. 2008 Mar;73(3):789-800. doi: 10.1124/mol.107.042101. Epub 2007 Dec 20.
3
A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5.
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5639-44. doi: 10.1073/pnas.090576697.
4
A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity.
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5698-703. doi: 10.1073/pnas.96.10.5698.
5
9
Interaction of small molecule inhibitors of HIV-1 entry with CCR5.
Virology. 2006 May 25;349(1):41-54. doi: 10.1016/j.virol.2006.01.018. Epub 2006 Feb 21.

引用本文的文献

1
Novel small synthetic HIV-1 V3 crown variants: CCR5 targeting ligands.
J Biochem. 2022 Sep 5;172(3):149-164. doi: 10.1093/jb/mvac052.
2
Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore-based virtual screening approach.
Eur J Pharm Sci. 2020 Dec 1;155:105537. doi: 10.1016/j.ejps.2020.105537. Epub 2020 Sep 2.
3
Status Presens of Antiviral Drugs And Strategies: Part I: DNA Viruses and Retroviruses.
Adv Antivir Drug Des. 2007;5:1-58. doi: 10.1016/S1075-8593(06)05001-5. Epub 2007 Sep 2.
4
CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion.
Cancer Res. 2018 Apr 1;78(7):1657-1671. doi: 10.1158/0008-5472.CAN-17-0915. Epub 2018 Jan 22.
5
Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5).
J Med Chem. 2015 Nov 12;58(21):8647-57. doi: 10.1021/acs.jmedchem.5b01245. Epub 2015 Oct 20.
7
Specificity for a CCR5 Inhibitor Is Conferred by a Single Amino Acid Residue: ROLE OF ILE198.
J Biol Chem. 2015 Apr 24;290(17):11041-51. doi: 10.1074/jbc.M115.640169. Epub 2015 Mar 12.
8
Targeting CCR5 for anti-HIV research.
Eur J Clin Microbiol Infect Dis. 2014 Nov;33(11):1881-7. doi: 10.1007/s10096-014-2173-0. Epub 2014 Jun 11.
9
Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.
PLoS One. 2013 Jun 6;8(6):e65207. doi: 10.1371/journal.pone.0065207. Print 2013.
10
Design, synthesis and biological evaluation of novel piperazine derivatives as CCR5 antagonists.
PLoS One. 2013;8(1):e53636. doi: 10.1371/journal.pone.0053636. Epub 2013 Jan 7.

本文引用的文献

4
New advances in HIV entry inhibitors development.
Curr Drug Targets Infect Disord. 2004 Dec;4(4):339-55. doi: 10.2174/1568005043340498.
5
Gateways to clinical trials.
Methods Find Exp Clin Pharmacol. 2004 May;26(4):295-318.
7
5th Antiviral Drug Discovery and Development Summit.
Expert Opin Investig Drugs. 2004 Aug;13(8):1065-9. doi: 10.1517/13543784.13.8.1065.
8
HIV co-receptors as targets for antiviral therapy.
Curr Top Med Chem. 2004;4(9):883-93. doi: 10.2174/1568026043388501.
10
Virus entry as a target for anti-HIV intervention.
Curr Med Chem. 2003 Sep;10(17):1617-32. doi: 10.2174/0929867033457098.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验