DESIGN AND SYNTHESIS OF NOVEL PSEUDOPEPTIDES

新型伪肽的设计与合成

• 批准号: 2182020
• 负责人: STEPHEN MARTIN
• 金额: $ 14.16万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2182020
• 关键词: X ray spectrometry; antiAIDS agent; antiarthritic agent; antineoplastics; chemical models; chemical substitution; computer simulation; conformation; cyclopropanes; drug design /synthesis /production; enkephalins; enzyme substrate analog; nuclear magnetic resonance spectroscopy; oligopeptides; peptide analog; peptide chemical synthesis; peptide structure; protein structure function; stereochemistry; synthetic peptide

The goal of this research is the invention, synthesis, and evaluation of conformationally constrained mimics of peptide secondary structure. The first generation of rigid dipeptide mimics that will be investigated is based upon 1,2,3-trisubstituted cyclopropanes as designated by the general term -Xaa psi[CP]Yaa-. The backbone substituents in these replacements may be disposed in either a cis or trans relationship on the cyclopropane ring, thereby locking the peptide backbone in either an extended beta- strand conformation or a beta-turn motif by constraining the phi or the psi angles, respectively. The chi1-angles are also restricted to direct the amino acid side chains in specific orientations corresponding approximately to the gauche(-), gauche(+), and anti (+ or - 80) conformations. New methods for the asymmetric synthesis of functionalized, trisubstituted cyclopropanes will be developed, and novel tactics will be invented that will facilitate their incorporation into pseudopeptides. The conformational effects of introducing extended and turned -Xaa psi(CP]Yaa,- mimics into peptides will be analyzed by modeling, NMR and X- ray studies. Cis -Xaa psi[CP]Yaa- isosteres will be substituted into analogues of oligopeptides that are known to adopt beta-turns in solution and/or in the solid state for comparative structural studies. X-Ray studies of inhibitors complexed with HIV-1 protease and stromelysin will be conducted in collaborations with Dr. John Erickson (NCI) and Dr. Jens Birkoft (Hoffmann LaRoche), respectively. The efficacy of these new replacements will be evaluated by incorporating them into derivatives of biologically active peptides and comparing their affinities with those of the parent ligands for the same enzyme active sites and receptors. Pseudopeptides that contain trans -Xaa psi[CP]Yaa- replacements to enforce a local a-strand structure will be tested as inhibitors of HIV-1 protease (AIDS), type IV collagenase (rheumatoid arthritis and cancer metastasis), and stromelysin. The enkephalins appear to bind to opioid receptors via a beta-turn, so cis -Xaa psi[CP]Yaa- subunits will be incorporated into enkephalin analogues to assess their ability to mimic the biologically active conformation of these neuropeptides. The tetrapeptide Cys-Val-Phe-Met (CVFM) seems to adopt a type I beta-turn when bound to farnesyltransferase, so the potential of cis -Xaa psi[CP]Yaa- replacements to mimic the biologically active conformation of CVFM analogues will also be investigated. Potential HIV-1 protease inhibitors will be assayed at Abbott Laboratories, and inhibitors of the matrix metalloproteinases collagenase and stromelysin will be evaluated at Procter & Gamble. Enkephalin analogues will be submitted to the NIDA for assays for opiate receptor affinity and functional activity profiles, and the CVFM analogues will be tested by Dr. James Marsters at Genentech.

这项研究的目标是发明、合成和评价 多肽二级结构的构象受限模拟。这个 将研究的第一代刚性二肽模拟物是 基于将军指定的1，2，3-三取代环丙烷 术语-xaa psi[CP]ya-.这些取代物中的主链取代基可以 以顺式或反式关系布置在环丙烷上 环，从而将肽骨架锁定在扩展的β- 链构象或β转角基序通过限制phi或 分别为PSI角。Ch1角也被限制为直角 特定取向的氨基酸侧链对应 大约为guche(-)、guchhe(+)和anti(+或-80) 构象。官能化的不对称合成新方法， 将开发三取代环丙烷，并将开发新的策略 发明了有助于将它们结合到假肽中的物质。 引入扩展XaA和转角XaA的构象效应 多肽的PSI(CP)YAA，-模拟物将通过建模、核磁共振和X- 雷在学习。顺式-xaa-psi[CP]yaa-异构体将被取代为 已知在溶液中采用β转角的寡肽的类似物 和/或处于固态，用于比较结构研究。X射线 HIV-1蛋白水解酶和基质分解酶Will复合抑制剂的研究 与约翰·埃里克森博士(NCI)和延斯博士合作进行 Birkoft(Hoffmann LaRoche)。 这些新替代品的效果将通过纳入 将它们转化为生物活性多肽的衍生物，并比较它们的 与同一酶活性的母体配体的亲和力 部位和受体。含有反式-xaa psi[CP]yaa-的假肽 用于加强局部a链结构的替换将进行如下测试 HIV-1蛋白酶(艾滋病)、IV型胶原酶(类风湿)的抑制剂 关节炎和癌症转移)，以及基质分解素。脑啡肽出现了 通过β-转折与阿片受体结合，所以顺式-xaa-psi[CP]yaa- 亚基将被纳入脑啡肽类似物中，以评估其 能够模拟这些化合物的生物活性构象 神经肽。四肽Cys-Val-Phe-Met(CVFM)似乎采用一种 当与法尼基转移酶结合时，I型β转角，所以 模拟生物活性的顺式-xaa-psi[CP]Yaa-取代物 还将研究CVFM类似物的构象。 雅培公司将测试潜在的HIV-1蛋白酶抑制剂 实验室和基质金属蛋白酶胶原酶抑制剂 而基质分解素将在宝洁进行评估。脑啡肽 类似物将提交给NIDA进行阿片受体检测 亲和力和功能活性图谱，CVFM类似物将是 由基因泰克的詹姆斯·马斯特斯博士测试。