改进病毒蛋白酶抑制剂以对抗耐药性。
Improving Viral Protease Inhibitors to Counter Drug Resistance.
作者信息
Kurt Yilmaz Nese, Swanstrom Ronald, Schiffer Celia A
机构信息
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Department of Biochemistry and Biophysics, and the UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
出版信息
Trends Microbiol. 2016 Jul;24(7):547-557. doi: 10.1016/j.tim.2016.03.010. Epub 2016 Apr 15.
Abstract
Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design.
摘要
耐药性是医疗保健中的一个主要问题，它破坏治疗效果，因此需要采用新的药物设计方法。对病毒蛋白酶抑制剂耐药性的广泛研究，特别是对HIV-1和丙型肝炎病毒（HCV）蛋白酶抑制剂耐药性的研究，揭示了大量关于耐药性背后的结构和分子机制的信息。这些见解催生了几种改进病毒蛋白酶抑制剂以对抗耐药性的策略，例如利用基本生物学功能和借助进化限制。将这些策略纳入基于结构的药物设计中，可以最大限度地降低对耐药性的易感性，不仅适用于病毒蛋白酶，也适用于其他快速进化的药物靶点，从而通过更智能、更合理的设计在进化之前一步设计抑制剂来对抗耐药性。
相似文献
1
Improving Viral Protease Inhibitors to Counter Drug Resistance.改进病毒蛋白酶抑制剂以对抗耐药性。
Trends Microbiol. 2016 Jul;24(7):547-557. doi: 10.1016/j.tim.2016.03.010. Epub 2016 Apr 15.
2
Molecular characterization of hepatitis C virus for determination of subtypes and detection of resistance mutations to protease inhibitors in a group of intravenous drug users co-infected with HIV.对一组合并感染 HIV 的静脉吸毒者进行丙型肝炎病毒的分子特征分析，以确定亚型并检测蛋白酶抑制剂耐药突变。
J Med Virol. 2015 Sep;87(9):1549-57. doi: 10.1002/jmv.24213. Epub 2015 May 1.
3
A hierarchical model of HIV-1 protease drug resistance.一种HIV-1蛋白酶耐药性的层次模型。
Appl Bioinformatics. 2002;1(1):3-12.
4
Hepatitis C virus (HCV) protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients.丙型肝炎病毒 (HCV) 蛋白酶变异性和 HIV/HCV 合并感染患者的抗 HCV 蛋白酶抑制剂耐药性。
HIV Med. 2011 Sep;12(8):506-9. doi: 10.1111/j.1468-1293.2011.00913.x. Epub 2011 Mar 16.
5
Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance.靶向蛋白质主链的HIV蛋白酶抑制剂设计：一种对抗耐药性的有效策略。
Acc Chem Res. 2008 Jan;41(1):78-86. doi: 10.1021/ar7001232. Epub 2007 Aug 28.
6
Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir.HIV-1蛋白酶抑制剂的耐药性耐受性：地瑞那韦概述
AIDS Rev. 2008 Jul-Sep;10(3):131-42.
7
Interview with Celia Schiffer.对西莉亚·希弗的采访。
Future Med Chem. 2013 Jul;5(11):1193-7. doi: 10.4155/fmc.13.106.
8
Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance.评估底物-囊泡假说：设计用于抵抗耐药性的新型 HIV-1 蛋白酶抑制剂的结构分析。
J Virol. 2010 May;84(10):5368-78. doi: 10.1128/JVI.02531-09. Epub 2010 Mar 17.
9
Evolving therapeutic paradigms for HIV and HCV.不断演变的HIV和HCV治疗模式。
Curr Opin Biotechnol. 2003 Dec;14(6):634-40. doi: 10.1016/j.copbio.2003.10.012.
10
Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection.现代药物研发中的挑战：以博赛匹韦为例，一种用于治疗丙型肝炎病毒感染的HCV蛋白酶抑制剂
Acc Chem Res. 2008 Jan;41(1):50-9. doi: 10.1021/ar700109k.
引用本文的文献
1
Boosting immunity: synergistic antiviral effects of luteolin, vitamin C, magnesium and zinc against SARS-CoV-2 3CLpro.增强免疫力：木犀草素、维生素 C、镁和锌对 SARS-CoV-2 3CLpro 的协同抗病毒作用。
Biosci Rep. 2024 Aug 28;44(8). doi: 10.1042/BSR20240617.
2
Predicting drug-Protein interaction with deep learning framework for molecular graphs and sequences: Potential candidates against SAR-CoV-2.基于分子图和序列的深度学习框架预测药物-蛋白相互作用：针对 SAR-CoV-2 的潜在候选药物。
PLoS One. 2024 May 10;19(5):e0299696. doi: 10.1371/journal.pone.0299696. eCollection 2024.
3
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.一种口服生物可利用的 SARS-CoV-2 主蛋白酶抑制剂，具有改善的亲和力和降低的突变敏感性。
Sci Transl Med. 2024 Mar 13;16(738):eadi0979. doi: 10.1126/scitranslmed.adi0979.
4
Contributions of Hyperactive Mutations in M from SARS-CoV-2 to Drug Resistance.SARS-CoV-2 M 区的活跃突变对药物耐药性的贡献。
ACS Infect Dis. 2024 Apr 12;10(4):1174-1184. doi: 10.1021/acsinfecdis.3c00560. Epub 2024 Mar 12.
5
Natural Polymorphisms D60E and I62V Stabilize a Closed Conformation in HIV-1 Protease in the Absence of an Inhibitor or Substrate.天然多态性 D60E 和 I62V 使 HIV-1 蛋白酶在没有抑制剂或底物的情况下稳定在封闭构象。
Viruses. 2024 Feb 2;16(2):236. doi: 10.3390/v16020236.
6
Metal-binding proteins and proteases in RNA viruses: unravelling functional diversity and expanding therapeutic horizons.金属结合蛋白和蛋白酶在 RNA 病毒中的作用：揭示功能多样性并拓展治疗前景。
J Virol. 2023 Dec 21;97(12):e0139923. doi: 10.1128/jvi.01399-23. Epub 2023 Nov 20.
7
Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir.结构-功能分析揭示了 HIV-1 CRF01_AE 对进入抑制剂替西拉韦耐药的关键分子决定因素。
Nat Commun. 2023 Oct 23;14(1):6710. doi: 10.1038/s41467-023-42500-2.
8
Non-Canonical Amino Acids in Analyses of Protease Structure and Function.非天然氨基酸在蛋白酶结构与功能分析中的应用。
Int J Mol Sci. 2023 Sep 13;24(18):14035. doi: 10.3390/ijms241814035.
9
Evolution of drug resistance drives destabilization of flap region dynamics in HIV-1 protease.耐药性的演变推动了HIV-1蛋白酶中瓣区动力学的不稳定。
Biophys Rep (N Y). 2023 Aug 10;3(3):100121. doi: 10.1016/j.bpr.2023.100121. eCollection 2023 Sep 13.
10
Systematic Analyses of the Resistance Potential of Drugs Targeting SARS-CoV-2 Main Protease.针对 SARS-CoV-2 主蛋白酶的药物耐药性的系统分析。
ACS Infect Dis. 2023 Jul 14;9(7):1372-1386. doi: 10.1021/acsinfecdis.3c00125. Epub 2023 Jun 30.
本文引用的文献
1
Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.丙型肝炎病毒NS3/4A抑制剂MK-5172中环化作用的结构和热力学效应
ACS Chem Biol. 2016 Apr 15;11(4):900-9. doi: 10.1021/acschembio.5b00647. Epub 2016 Jan 6.
2
Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial.蛋白酶抑制剂单药疗法用于长期管理HIV感染：一项随机、对照、开放标签、非劣效性试验。
Lancet HIV. 2015 Oct;2(10):e417-26. doi: 10.1016/S2352-3018(15)00176-9. Epub 2015 Sep 14.
3
Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms.耐药性的进化后果：不同靶点和生物的共同原则。
Nat Rev Genet. 2015 Aug;16(8):459-71. doi: 10.1038/nrg3922. Epub 2015 Jul 7.
4
Interferon-free, direct-acting antiviral therapy for chronic hepatitis C.用于慢性丙型肝炎的无干扰素直接抗病毒疗法。
J Viral Hepat. 2015 Nov;22(11):861-70. doi: 10.1111/jvh.12422. Epub 2015 Jun 17.
5
Defective hydrophobic sliding mechanism and active site expansion in HIV-1 protease drug resistant variant Gly48Thr/Leu89Met: mechanisms for the loss of saquinavir binding potency.HIV-1蛋白酶耐药变体Gly48Thr/Leu89Met中疏水性滑动机制缺陷和活性位点扩展：沙奎那韦结合效力丧失的机制
Biochemistry. 2015 Jan 20;54(2):422-33. doi: 10.1021/bi501088e. Epub 2015 Jan 7.
6
Genetic barrier to resistance for dolutegravir.对多替拉韦的耐药性的遗传屏障。
AIDS Rev. 2015 Jan-Mar;17(1):56-64.
7
Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial.在无肝硬化或伴有肝硬化的既往无应答的患者中，使用格拉瑞韦（MK-5172）和艾尔巴韦（MK-8742）联合或不联合利巴韦林治疗 12 周与 18 周对丙型肝炎病毒基因型 1 感染的疗效和安全性（C-WORTHY）：一项随机、开放标签的 2 期临床试验。
Lancet. 2015 Mar 21;385(9973):1075-86. doi: 10.1016/S0140-6736(14)61795-5. Epub 2014 Nov 11.
8
Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.HIV-1蛋白酶耐药性中Gag底物协同进化的结构基础及远端效应
Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):15993-8. doi: 10.1073/pnas.1414063111. Epub 2014 Oct 29.
9
Structural analysis of asunaprevir resistance in HCV NS3/4A protease.丙型肝炎病毒NS3/4A蛋白酶中阿舒瑞韦耐药性的结构分析
ACS Chem Biol. 2014 Nov 21;9(11):2485-90. doi: 10.1021/cb5006118. Epub 2014 Sep 30.
10
Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease.耐药性突变改变与抑制剂结合的HIV-1蛋白酶的动力学。
J Chem Theory Comput. 2014 Aug 12;10(8):3438-3448. doi: 10.1021/ct4010454. Epub 2014 Jun 12.
Zotero 插件