Novel Bioactive Conformation Constructed by Structurally Constrained CH/π Interaction between Amino Acids Side Chains

烷基（CH供体）和苯环（π供体）之间的CH/π相互作用是一种氢键，对构建蛋白质的特殊三维结构具有重要意义。本研究的目的是建立一种新的方法来限制肽的生物活性构象，通过构建这样的氨基酸侧链之间的CH/π相互作用，以创建一个新的生物活性肽。CH/π相互作用应该成为疏水核心的结构要素。具有D-L构型的二肽Leu-Phe在Leu-异丁基和Phe-苯基之间构建了典型的CH/π相互作用。该二肽具有N-末端游离氨基和C-末端游离羧基。如果我们能够加载一个结构元件来诱导与靶肽或蛋白质分子的特异性相互作用，那么该衍生物将是一种新型的激动剂，靶点的抑制剂。我们已经成功地设计和合成了SPE ...更多信息 通过将一个基团结合到每种酶的底物识别位点上，来制备一系列丝氨酸蛋白酶的特异性抑制剂。当苄基与C-末端羧基结合时，发现所得的D-Leu-Phe苄基酰胺是胰凝乳蛋白酶的强抑制剂。当苄基的仲氢被胍基取代时，衍生物对胰凝乳蛋白酶没有抑制作用。相反，它强烈抑制胰蛋白酶，另一种类型的丝氨酸蛋白酶。因此，新合成了几个系列的胰蛋白酶和胰凝乳蛋白酶抑制剂的化合物。结果清楚地表明，二肽单元D-Leu-Phe可以作为一个结构核心负载一个元素，作为一个新的生物活性肽的功能。为加强CH/π相互作用，寻找更适合作为CH供体或π供体的结构具有重要意义。作为CH供体，我们设计了一系列氨基酸，其侧链含有甲胺基团，（-N）CH 3 n（n=1，2和3）。此外，我们还合成了苯基氢被卤素取代的强π供体苯丙氨酸衍生物。例如，间溴-对氟苯丙氨酸在2位掺入该SFLLRNP时，使凝血酶受体栓系的配体肽SFLLRNF的活性增加约6倍。这显然是一种通过加强结构限制的CH/π相互作用来提高活性的新途径。因此，该研究项目的主要目标实现了巨大的科学成就。少

The CH/π interaction between alkyl group (CH donor) and benzene ring (π donor) is a kind of hydrogen bondings, and is important to construct a particular three-dimensional structure of proteins. The goal of the present study is to establish a novel method to constrain the bioactive conformation of peptides by constructing such a CH/π interaction between amino acid side chains in order to create a novel biologically active peptide. The CH/π interaction should become a structural essential with the hydrophobic core. Dipeptide Leu-Phe with the D-L configurational sequence constructs a typical CH/π interaction between Leu-isobutyl group and Phe-phenyl group. This dipeptide has a N-terminal free amino group and a C-terminal free carboxyl group. If we are able to load a structural element to induce a specific interaction with the target peptide or protein molecule(s), the derivative would be a new type of agonist, inhibitors of the target. We have succeeded in the design and synthesis of spe … More cific inhibitors of a series of serine proteases by conjugating a group that binds to the substraterecognition site of each enzyme. When the benzyl group was combined to the C-terminal carboxyl group, the resulting D-Leu-Phe benzyl amide was found to be a strong inhibitor of chymotrypsin. When the para-hydrogen of this benzyl group was replaced by the guanidine group, the derivative showed no inhibition for chymotrypsin. Instead, it strongly inhibited trypsin, another type serine protease. Thus, several series of compounds were newly synthesized as inhibitors of trypsin and chymotrypsin. The results clearly indicate that the dipeptide unit D-Leu-Phe can be a structural core to load an element to function as a novel bioactive peptide. The procedure employed in this study will definitely open a new field in the structure-activity studies of peptide sciences.In order to strengthen the CH/π interaction, it is important to search the structures more suitable as a CH donor or as a π donor. As CH donors we have designed a series of amino acids, the side chains of which contain the methylamine group, (-N)CH3n (n=1, 2, and 3). In addition, we achieved the synthesis of the phenylalanine derivatives, as strong π donors the phenylhydrogens of which were substituted with halogens. For instance, meta-bromo-para-fluorophenylalanine increased the activity of thrombin receptor-tethered ligand peptide SFLLRNF about six times when it was incorporated into this SFLLRNP at position 2. Apparently, this is a new way to enhance the activity by reinforcing the structurally restricted CH/π interaction. Thus, the major goal of this research project was achieved with enormous scientific successes. Less