Development of anti-HIV-1 peptides based on the concept of the discrimination of helical surfaces

基于螺旋面区分概念的抗HIV-1肽的开发

• 批准号: 15390037
• 负责人: OTAKA Akira
• 金额: $ 7.55万
• 依托单位: The University of Tokushima (2005)Kyoto University (2003-2004)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390037/
• 关键词: HIV-1; α-helix; membrane fusion; anti-viral agents; peptide; SARS-CoV; a-helix; SARS

We have been confronted with epidemic threat of infectious disease caused by emerging mortal viruses including HIV-1 and SARS-CoV. A general strategy for development of anti-viral drugs targeting at a common infection machinery has been desired, which provides new methodologies for the prevention and treatment of other newly emerging viruses. Among several infection machineries, membranes fusion steps between viruses and target cells are potential targets. A wide variety of viruses are presumed to establish their cell/virus membranes fusion by formation of supramolecular structures of Env proteins of the viruses. For example, membrane fusion of HIV-1 and target cells has been well known to be mediated by formation of a six-helix bundle resulting from the coiled-coil interaction between highly α-helical N-(or heptad repeat 1:HR1) and C (or heptad repeat 2:HR2)-region in the extracellular domain of gp41 (HIV-1 Env protein). And compounds inhibiting the formation of the six-helix bundle s … More tructure in the HIV-1 infection step are well known to work as an anti-HIV-1 drug. We have remodeled the α-helical C-region (HR2)-derived peptides to develop an efficient anti-HIV-1 peptide and found that incorporation of replacement by artificial heptad sequence, X-EE-XX-KK (X=amino acid residues responsible for the interaction with N-(or HR1) region ; E=Glu ; K=Lys), into the C-region of gp41 allowed the remodeled peptides with enhanced α-helicity to exhibit high anti-HIV-1 activity. On the basis of development of this highly effective anti-HIV-1 peptide, we expected that this remodeling strategy, (referred to as X-EE-XX-KK concept), would be widely applicable to other virus using fusion machinery similar to gp41 of HIV-1. Spike (S) protein (Env protein) of SARS-CoV is supposed to be involved in the fusion process in a way to similar to gp41. We applied the same strategy using the X-EE-XX-KK concept to potential α-helical sequence (HR2 region) of the S protein, and found the designed peptides exhibit strong anti-SARS-CoV activity. Less

我们面临着HIV-1、SARS-CoV等新出现的致命病毒引起的传染病流行威胁。开发针对常见感染机制的抗病毒药物的总体战略已被需要，这为预防和治疗其他新出现的病毒提供了新的方法。在几种感染机制中，病毒与靶细胞之间的膜融合步骤是潜在的目标。据推测，各种各样的病毒都是通过形成病毒Env蛋白的超分子结构来建立细胞/病毒膜融合的。例如，众所周知，HIV-1和靶细胞的膜融合是由gp41 （HIV-1 Env蛋白）胞外结构域中高α-螺旋N-（或七肽重复1:HR1）和C（或七肽重复2:HR2）区域之间的螺旋相互作用形成的六螺旋束介导的。在HIV-1感染过程中，抑制六螺旋束形成的化合物被认为是一种抗HIV-1药物。我们重塑了α-螺旋c区（HR2）衍生的肽，以开发有效的抗hiv -1肽，并发现人工七肽序列，X- ee - xx - kk (X=负责与N-（或HR1）区相互作用的氨基酸残基；E = Glu;K=Lys)，进入gp41的c区，使得具有增强α-螺旋度的重塑肽表现出高的抗hiv -1活性。基于这种高效抗HIV-1肽的开发，我们期望这种重构策略（称为X-EE-XX-KK概念）将广泛适用于使用类似HIV-1的gp41融合机制的其他病毒。SARS-CoV的Spike (S)蛋白（Env蛋白）可能以类似gp41的方式参与融合过程。我们利用X-EE-XX-KK概念对S蛋白的潜在α-螺旋序列（HR2区）应用相同的策略，发现设计的肽具有较强的抗sars - cov活性。少

项目成果

Akira Otaka et al.: "Application of Samarium Diiodide (SmI_2)-induced Reduction of γ-Acetoxy-α,β-enoates with α-Specific Kinetic Electrophilic Trapping for the Synthesis of Amino Acid Derivatives"Chem.Commun.. 1834-1835 (2003)

Akira Otaka 等人：“应用二碘化钐 (SmI_2) 诱导的 γ-乙酰氧基-α,β-烯酸酯还原与 α-特异性动力学亲电捕获来合成氨基酸衍生物”Chem.Commun. 1834-1835 (2003)

Hirokazu Tamamura et al.: "Enhancement of the T140-based Pharmacophores Leads to the Development of More Potent and Bio-stable CXCR4 Antagonists"Org.Biomol.Chem.. 1. 3663-3669 (2003)

Hirokazu Tamamura 等人：“基于 T140 的药效团的增强导致了更有效和生物稳定的 CXCR4 拮抗剂的开发”Org.Biomol.Chem.. 1. 3663-3669 (2003)

Synthesis of Potent β-Secretase Inhibitors Containing a Hydroxyethylamine Dipeptide Isostere and Their Structure-activity Relationship Studies

含羟乙胺二肽等排体的强效β-分泌酶抑制剂的合成及其构效关系研究

• 发表时间: 2003
• 期刊: Org. Biomol. Chem. 1巻
• 作者: H.Tamamura;N.Yamamoto;A.Otaka;Akira Otaka et al.;Akira Otaka et al.;Akira Otaka et al.;H.Tamamura;A.Otaka;H.Tamamura
• 通讯作者: H.Tamamura

Akira Otaka et al.: "SmI_2-Mediated Reduction of γ,γ-Difluoro-α,β-enoates with Application to the Synthesis of Functionalized (Z)-Fluoroalkene Type Dipeptide Isosteres"J.Org.Chem.. 69. 1634-1645 (2004)

Akira Otaka 等人：“SmI_2 介导的 γ,γ-二氟-α,β-烯酸酯还原及其在功能化 (Z)-氟烯烃型二肽等排体合成中的应用”J.Org.Chem.. 69. 1634- 1645 (2004)

Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives.

• DOI: 10.1039/b306473p
• 发表时间: 2003-10
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: H. Tamamura;K. Hiramatsu;S. Kusano;S. Terakubo;N. Yamamoto;J. Trent;Zixuan Wang;S. Peiper;H. Nakashima;A. Otaka;N. Fujii