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    PEPTIDE INHIBITOR OF HIV REVERSE TRANSCRIPTION
    1.
    发明申请
    PEPTIDE INHIBITOR OF HIV REVERSE TRANSCRIPTION 有权
    艾滋病毒逆转录病毒肽抑制剂

    公开(公告)号：US20160257715A1

    公开(公告)日：2016-09-08

    申请号：US15030739

    申请日：2014-10-21

    申请人： THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK

    发明人： Paul F. AGRIS ,  Carol HALL ,  Xingqing XIAO

    IPC分类号： C07K7/08

    CPC分类号： C07K7/08 ,  A61K38/00

    摘要： Disclosed are peptides that exhibit good binding to the anticodon stem and loop (ASL) of human lysine tRNA species, tRNALys3. Using a search algorithm combining Monte Carlo (MC) and self-consistent mean field (SCMF) techniques, the peptides were evolved a with the ultimate purpose of using them to break the replication cycle of HIV-1 virus. The starting point was the 15-amino-acid sequence, RVTHHAFLGAHRTVG, found experimentally to bind selectively to hypermodified tRNALys3. The peptide backbone conformation was determined via atomistic simulation of the peptide-ASLLys3 complex and then held fixed throughout the search. The proportion of amino acids of various types (hydrophobic, polar, charged, etc.) was varied to mimic different peptide hydration properties. Three different sets of hydration properties were examined in the search algorithm to see how this affects evolution to the best-binding peptide sequences. Certain amino acids are commonly found at fixed sites for all three hydration states, some necessary for binding affinity and some necessary for binding specificity. Analysis of the binding structure and the various contributions to the binding energy shows that: 1) two hydrophilic residues (asparagine (ASN) at site 11 and the cysteine (CYS) at site 12) “recognize” the ASLLys3 due to the VDW energy, and thereby contribute to its binding specificity, and 2) the positively-charged arginines (ARG) at sites 4 and 13 preferentially attract the negatively-charged sugar rings and the phosphate linkages, and thereby contribute to the binding affinity.

    摘要翻译： 公开了与人赖氨酸tRNA物种tRNALys3的反密码子茎和环（ASL）表现出良好结合的肽。 使用组合蒙特卡罗（MC）和自我一致平均场（SCMF）技术的搜索算法，演化了一个最终目的，最终目的是打破HIV-1病毒复制周期。 起始点是15个氨基酸序列，RVTHHAFLGAHRTVG，通过实验结果可以选择性地结合超调型tRNALys3。 通过肽-ASLLys3复合​​物的原子模拟确定肽骨架构象，然后在整个搜索中保持固定。 各种类型的氨基酸（疏水性，极性，带电荷等）的比例变化以模拟不同的肽水合性质。 在搜索算法中检查了三组不同的水合特性，以了解它如何影响最佳结合肽序列的进化。 对于所有三种水合状态，通常在固定位点发现某些氨基酸，一些必需的结合亲和力和一些必需的结合特异性。 结合结构的分析和对结合能的各种贡献表明：1）两个亲水残基（位点11处的天冬酰胺（ASN）和位点12处的半胱氨酸（CYS））由于VDW能量“识别”ASLLys3， 从而有助于其结合特异性，以及2）位点4和13处带正电的精氨酸（ARG）优先吸引带负电荷的糖环和磷酸键，从而有助于结合亲和力。