A Flexible Approach to Inhibiting HIV NCp7

抑制 HIV NCp7 的灵活方法

基本信息

批准号：
9008023
负责人：
Katherine L Seley-Radtke
金额：
$ 19.09万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE COUNTY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-05 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9008023
关键词：
Adverse effects Antiviral Agents Area Automobile Driving Binding Biological Biological Testing Complex Computer Simulation DNA Drug Targeting Enzymes Exhibits Future Generations Genome Guanosine HIV HIV-1 Hand Health Highly Active Antiretroviral Therapy Laboratories Left Literature Modeling Modification Molecular Conformation Multi-Drug Resistance Mutation Nucleocapsid Proteins Nucleosides Play Polyproteins Procedures Process Protein Structure Initiative Proteins RNA RNA Binding Replication-Associated Process Reporting Research Resistance Resistance development Reverse Transcription Role Route Series Specificity Staging Structure Testing Therapeutic Titrations Toxic effect Transfer RNA Viral Virus Replication Zinc Zinc Fingers analog base cytotoxicity design drug development flexibility global health inhibitor/antagonist model design molecular dynamics mutant nucleobase research study resistant strain screening small molecule inhibitor student training virtual zinc-binding protein

项目摘要

DESCRIPTION (provided by applicant): The extensive use of antiviral drugs has resulted in the emergence of mutant viral strains that are resistant to the currently available nucleoside therapeutics. Using a combination of drugs that target different viral enzymes (termed highly active anti-retroviral therapy or HAART) has helped, however undesirable side effects and toxicity are often prevalent and reports of multidrug resistance are increasing. As a result, the need for new viral enzymatic targets is critical. In that regard, the nucleocapsid protein of HIV offers forth an attractive target. NCp7 is a small zinc-binding protein that has been shown to be critical in both the early and late stages of the HIV-1 replication process. NCp7 (and the NCp7 domain of the Gag precursor polyprotein) has several key roles in HIV replication, including direct participation in RNA genome recognition and packaging, promoting annealing of the tRNA primer to initiate reverse transcription, and facilitating strand transfer during reverse transcription. NCp7 contains two CCHC-type zinc finger domains that play critical RNA-binding roles during replication, and single-atom Cys-to-Ser mutations that disrupt zinc coordination are sufficient to completely block viral replication. Several approaches to designing inhibitors have been tried, most commonly, use of zinc-ejectors, however to date these have exhibited significant toxicity and poor specificity. A problem that has hindered the identification of viable inhibitors is the inherent flexibility of the protein itself. As such, flexible nucleosides, known s "fleximers" designed and developed in the Seley-Radtke laboratory may provide a solution. In that regard, a series of flexible nucleobase ("flexbase") inhibitors of NCp7 have been identified by means of a virtual screening process. The flexbase analogues are in excellent alignment with the central guanosine residue known to be critical to the biologically relevant conformations of NCp7, thus form the basis for this application. Notably, the flexbases should not result in zinc ejection thereby overcoming the problems associated with other approaches.

描述（申请人证明）：广泛使用抗药药导致了突变病毒菌株的出现，目前可用的侧面治疗有助于新的病毒酶考虑到HIB的核蛋白质蛋白具有有吸引力的靶标的NCP7。复制，包括直接参与RNA基因组识别和包装，促进tRNA底漆的退火以启动反向，并促进Stransfer durse durse转录。最常见的是使用锌的抑制剂。抑制剂是蛋白质本身的固有，在这方面，已知的fleximers''已知的中央鸟通对NCP7的生物学相关性至关重要，因此形成了著名的弹性。