GS-8374，一种含膦酸酯的 HIV-1 蛋白酶的原型抑制剂，能够有效抑制具有氨基酸插入的蛋白酶突变体。
GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions.
机构信息
Gilead Sciences and IOCB Research Center, Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
出版信息
J Virol. 2014 Mar;88(6):3586-90. doi: 10.1128/JVI.02688-13. Epub 2013 Dec 26.
Abstract
Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.
摘要
插入蛋白酶（PR）区域的人类免疫缺陷病毒（HIV）代表了一种针对 HIV PR 抑制剂（PI）的抗病毒耐药的有趣机制。在这里，我们证明了含有膦酸酯的实验性 HIV PI GS-8374 相对于其他 PI 具有更高的能力，可有效抑制携带 PR 插入和许多其他突变的患者源性重组 HIV 株。我们将酶抑制与相应的重组 PR 的体外催化活性相关联，并提供 PR-抑制剂复合物的生化和结构分析。
相似文献
1
GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions.GS-8374，一种含膦酸酯的 HIV-1 蛋白酶的原型抑制剂，能够有效抑制具有氨基酸插入的蛋白酶突变体。
J Virol. 2014 Mar;88(6):3586-90. doi: 10.1128/JVI.02688-13. Epub 2013 Dec 26.
2
Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region.99个还不够：对在翼片区域有插入的耐抑制剂的1型人类免疫缺陷病毒蛋白酶突变体的分子特征分析
J Virol. 2008 Jun;82(12):5869-78. doi: 10.1128/JVI.02325-07. Epub 2008 Apr 9.
3
Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir.对蛋白酶抑制剂地瑞那韦耐药的人类免疫缺陷病毒临床分离株的分子特征分析
J Virol. 2009 Sep;83(17):8810-8. doi: 10.1128/JVI.00451-09. Epub 2009 Jun 17.
4
Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme.临床抑制剂与合理选择的多药耐药HIV-1蛋白酶模型前体的结合明显弱于与释放的成熟酶的结合。
Biochemistry. 2016 Apr 26;55(16):2390-400. doi: 10.1021/acs.biochem.6b00012. Epub 2016 Apr 15.
5
Structural insights into the South African HIV-1 subtype C protease: impact of hinge region dynamics and flap flexibility in drug resistance.南非 HIV-1 亚型 C 蛋白酶的结构研究：铰链区动力学和瓣灵活性对耐药性的影响。
J Biomol Struct Dyn. 2013 Dec;31(12):1370-80. doi: 10.1080/07391102.2012.736774. Epub 2012 Nov 12.
6
Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants.HIV-1耐药性发展的分子分析：奈非那韦耐药HIV蛋白酶突变体的酶活性、晶体结构和热力学
J Mol Biol. 2007 Dec 7;374(4):1005-16. doi: 10.1016/j.jmb.2007.09.083. Epub 2007 Oct 3.
7
In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile.在体外对 GS-8374 进行表征，GS-8374 是一种新型含膦酸酯的 HIV-1 蛋白酶抑制剂，具有良好的耐药性特征。
Antimicrob Agents Chemother. 2011 Apr;55(4):1366-76. doi: 10.1128/AAC.01183-10. Epub 2011 Jan 18.
8
TMC310911, a novel human immunodeficiency virus type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors.TMC310911，一种新型的人类免疫缺陷病毒 1 型蛋白酶抑制剂，与目前的蛋白酶抑制剂相比，具有改善的体外耐药谱和更高的耐药遗传屏障。
Antimicrob Agents Chemother. 2011 Dec;55(12):5723-31. doi: 10.1128/AAC.00748-11. Epub 2011 Sep 6.
9
Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I.带有 HIV-1 蛋白酶耐药突变 V32I、I47V 和 V82I 的抗病毒抑制剂的结构研究。
Biochem Biophys Res Commun. 2019 Jun 30;514(3):974-978. doi: 10.1016/j.bbrc.2019.05.064. Epub 2019 May 12.
10
Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.无机多面体金属碳硼烷HIV蛋白酶抑制剂：克服抗病毒耐药性的新方法。
J Med Chem. 2008 Aug 14;51(15):4839-43. doi: 10.1021/jm8002334. Epub 2008 Jul 4.
引用本文的文献
1
Effect of polarization on HIV-1protease and fluoro-substituted inhibitors binding energies by large scale molecular dynamics simulations.通过大规模分子动力学模拟研究极化对 HIV-1 蛋白酶和氟取代抑制剂结合能的影响。
Sci Rep. 2017 Feb 3;7:42223. doi: 10.1038/srep42223.
2
Highly resistant HIV-1 proteases and strategies for their inhibition.高度耐药的HIV-1蛋白酶及其抑制策略。
Future Med Chem. 2015;7(8):1023-38. doi: 10.4155/fmc.15.44.
3
Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir.耐药性突变对HIV-1蛋白酶动力学特性的影响以及安普那韦和达芦那韦的抑制作用。
Sci Rep. 2015 May 27;5:10517. doi: 10.1038/srep10517.
本文引用的文献
1
Molecular basis of human immunodeficiency virus type 1 drug resistance: overview and recent developments.人类免疫缺陷病毒 1 型耐药性的分子基础：概述和最新进展。
Antiviral Res. 2013 Apr;98(1):93-120. doi: 10.1016/j.antiviral.2013.01.007. Epub 2013 Feb 8.
2
Human Immunodeficiency Virus Gag and protease: partners in resistance.人类免疫缺陷病毒 Gag 和蛋白酶：耐药的伙伴。
Retrovirology. 2012 Aug 6;9:63. doi: 10.1186/1742-4690-9-63.
3
Current and Novel Inhibitors of HIV Protease.当前和新型 HIV 蛋白酶抑制剂。
Viruses. 2009 Dec;1(3):1209-39. doi: 10.3390/v1031209. Epub 2009 Dec 11.
4
A first case of protease codon 35 amino acid insertion in a HIV-1 subtype B sequence detected in the Bauru region, state of São Paulo, Brazil: case report.巴西圣保罗州包鲁地区发现的 HIV-1 亚型 B 序列中蛋白酶 35 位氨基酸插入的首例病例：病例报告。
Rev Soc Bras Med Trop. 2011 May-Jun;44(3):392-4. doi: 10.1590/s0037-86822011000300027.
5
In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile.在体外对 GS-8374 进行表征，GS-8374 是一种新型含膦酸酯的 HIV-1 蛋白酶抑制剂，具有良好的耐药性特征。
Antimicrob Agents Chemother. 2011 Apr;55(4):1366-76. doi: 10.1128/AAC.01183-10. Epub 2011 Jan 18.
6
Long-term follow-up of 11 protease inhibitor (PI)-naïve and PI-treated HIV-infected patients harbouring virus with insertions in the HIV-1 protease gene.11 例未接受过蛋白酶抑制剂（PI）治疗和已接受过 PI 治疗且携带 HIV-1 蛋白酶基因插入的 HIV 感染患者的长期随访结果。
HIV Med. 2011 Mar;12(3):138-44. doi: 10.1111/j.1468-1293.2010.00862.x. Epub 2010 Aug 15.
7
Detection of the protease codon 35 amino acid insertion in sequences from treatment-naïve HIV-1 subtype C infected individuals in the Central Region of Portugal.在葡萄牙中部地区未经治疗的HIV-1 C亚型感染个体的序列中检测蛋白酶密码子35氨基酸插入情况。
J Clin Virol. 2009 Oct;46(2):169-72. doi: 10.1016/j.jcv.2009.06.019. Epub 2009 Jul 22.
8
Molecular epidemiology and divergence of HIV type 1 protease codon 35 inserted strains among treatment-naive patients in Hong Kong.香港初治患者中1型人类免疫缺陷病毒蛋白酶密码子35插入毒株的分子流行病学及分化情况
AIDS Res Hum Retroviruses. 2008 Apr;24(4):537-42. doi: 10.1089/aid.2007.0231.
9
Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region.99个还不够：对在翼片区域有插入的耐抑制剂的1型人类免疫缺陷病毒蛋白酶突变体的分子特征分析
J Virol. 2008 Jun;82(12):5869-78. doi: 10.1128/JVI.02325-07. Epub 2008 Apr 9.
10
Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants.HIV-1耐药性发展的分子分析：奈非那韦耐药HIV蛋白酶突变体的酶活性、晶体结构和热力学
J Mol Biol. 2007 Dec 7;374(4):1005-16. doi: 10.1016/j.jmb.2007.09.083. Epub 2007 Oct 3.
Zotero 插件