HIV Interactions In Viral Evolution

病毒进化中的艾滋病毒相互作用

• 批准号: 10242900
• 负责人: Stefan G Sarafianos
• 金额: $ 534.03万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242900
• 关键词: AIDS/HIV problem; Address; Antiviral resistance; Automobile Driving; Biochemical; Biological; Biological Process; Biophysics; Capsid; Chemicals; Chemistry; Complex; Computational Biology; Drug resistance; Event; Evolution; Genetic Structures; Goals; HIV; HIV drug resistance; Integrase; Lead; Life Cycle Stages; Mutation; Polyproteins; Proteins; RNA-Directed DNA Polymerase; Research; Research Personnel; Reverse Transcription; Role; Shapes; Structural Models; Structure; Synthesis Chemistry; System; Viral; Viral Physiology; Virus; Virus Integration; base; design; experience; fitness; insight; macromolecule; new therapeutic target; novel; pleiotropism; pol Gene Products; predictive modeling; programs; resistance mutation; small molecule; targeted treatment; virology

The HIV Interaction in Viral Evolution (HIVE) Center came together a little more than four years ago to understand, at the atomic, biophysical and evolutionary level, the system interdependency of interacting HIV macromolecules and their assemblies which shape the HIV life cycle. To accomplish this goal the proposed program will continue to explore the structural and biophysical interactions of HIV Gag and Gag-Pol polyproteins, capsid, reverse transcriptase, and integrase and their evolutionary relationships. The Center's research focus will also extend to cellular factors that inform the structural and macromolecular dynamics of events in reverse transcription, assembly, and integration. This will include studies on how APOBEC3 proteins suppress reverse transcription, and the role of LEDGF in guiding viral integration and its contribution to latency in conjunction with CPSF6. Studies on HIV drug resistance will tie together a genetic and structural perspective, based on mutational correlations that are due to constraints on protein structural stability and function and which ultimately shape fitness. The depth of the computational strength of the program is centered on expanding structural, biophysical, and viral sequencing findings for developing predictive structural models and small molecule probes targeting viral function. The strength of the Center's biological and computational research will provide insights into the interrelationships of viral and host mechanisms, enabling discovery of new drug targets and therapeutic strategies that may ultimately lead to a cure. The HIVE Center comprises a group of highly collaborative investigators with deep experience in HIV research and well established expertise in structural, biophysical, biochemical, and computational biology, as well as synthetic chemistry, and virology. They will study the mechanistic implications of viral and viral-host macromolecular interactions along with the dynamics and the impacts of the evolution of drug resistance to address relevant biological questions with the following Specific Aims: AIM1: Defining HIV polyproteins and their components in retroviral assembly and maturation AIM 2: Determining HIV-host interactions driving virus reverse transcription and integration AIM 3: Understanding evolution of antiviral resistance mutations and their biological and biophysical implications through studies AIM 4: Developing and characterizing novel small molecule probes to understand biological function

病毒进化中的艾滋病毒相互作用(HIVE)中心在四年多前成立， 在原子、生物物理和进化层面上理解相互作用的艾滋病毒的系统相互依存关系 塑造艾滋病毒生命周期的大分子及其组装。为了实现这一目标，提出了 该计划将继续探索HIV Gag和Gag-Pol多蛋白的结构和生物物理相互作用， 衣壳、逆转录酶和整合酶及其进化关系。该中心的研究重点 也将延伸到细胞因素，这些因素反过来通知事件的结构和大分子动力学 转录、组装和整合。这将包括对APOBEC3蛋白如何抑制逆转的研究 转录，以及LEDGF在指导病毒整合中的作用及其对潜伏期的贡献 CPSF6.对艾滋病毒耐药性的研究将从基因和结构角度结合起来，基于突变 由于对蛋白质结构稳定性和功能的限制而最终形成的相关性 健身。该程序的计算强度的深度集中在扩展结构、生物物理、 和病毒测序结果，用于开发预测性结构模型和小分子探针靶向 病毒功能。该中心的生物和计算研究的优势将提供对 病毒和宿主机制的相互关系，使发现新的药物靶点和治疗成为可能 可能最终导致治愈的策略。蜂巢中心由一组高度协作的 调查人员在艾滋病毒研究方面有丰富的经验，在结构、生物物理、 生物化学、计算生物学、合成化学和病毒学。他们将研究 病毒和病毒-宿主大分子相互作用的机制含义以及动力学和 耐药性的演变对解决以下具体生物学问题的影响 目标： AIM1：确定逆转录病毒组装和成熟过程中的HIV多蛋白及其组分 目标2：确定驱动病毒逆转录和整合的艾滋病毒-宿主相互作用 目标3：了解抗病毒耐药突变的进化及其生物学和生物物理 通过研究得出的启示 目的4：开发和表征了解生物功能的新型小分子探针

项目成果

Selective and Effective: Current Progress in Computational Structure-Based Drug Discovery of Targeted Covalent Inhibitors.

• DOI: 10.1016/j.tips.2020.10.005
• 发表时间: 2020-12
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Bianco G;Goodsell DS;Forli S
• 通讯作者: Forli S

Two structural switches in HIV-1 capsid regulate capsid curvature and host factor binding.

• DOI: 10.1073/pnas.2220557120
• 发表时间: 2023-04-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Stacey, James C. V.;Tan, Aaron;Lu, John M.;James, Leo C.;Dick, Robert A.;Briggs, John A. G.
• 通讯作者: Briggs, John A. G.

The SMC5/6 complex compacts and silences unintegrated HIV-1 DNA and is antagonized by Vpr.

• DOI: 10.1016/j.chom.2021.03.001
• 发表时间: 2021-05-12
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Dupont L;Bloor S;Williamson JC;Cuesta SM;Shah R;Teixeira-Silva A;Naamati A;Greenwood EJD;Sarafianos SG;Matheson NJ;Lehner PJ
• 通讯作者: Lehner PJ

Massive-Scale Binding Free Energy Simulations of HIV Integrase Complexes Using Asynchronous Replica Exchange Framework Implemented on the IBM WCG Distributed Network

• DOI: 10.1021/acs.jcim.8b00817
• 发表时间: 2019-04-01
• 期刊: JOURNAL OF CHEMICAL INFORMATION AND MODELING
• 影响因子: 5.6
• 作者: Xia，Junchao;Flynn，William;Levy，Ronald M.
• 通讯作者: Levy，Ronald M.

Halo Library, a Tool for Rapid Identification of Ligand Binding Sites on Proteins Using Crystallographic Fragment Screening.

• DOI: 10.1021/acs.jmedchem.2c01681
• 发表时间: 2023-05-11
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Chopra, Ashima;Bauman, Joseph D.;Ruiz, Francesc X.;Arnold, Eddy
• 通讯作者: Arnold, Eddy