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

我们面临着由包括 HIV-1 和 SARS-CoV 在内的新兴致命病毒引起的传染病的流行威胁，需要针对常见感染机制开发抗病毒药物的总体策略，这为治疗提供了新的方法。在多种感染机制中，病毒和靶细胞之间的膜融合步骤被认为是通过形成Env蛋白的超分子结构来建立其细胞/病毒膜融合。病毒。例如，众所周知，HIV-1 和靶细胞的膜融合是通过高度 α 螺旋 N-（或七肽重复序列 1：HR1）和 C 之间的卷曲螺旋相互作用形成六螺旋束来介导的（或七肽重复 2：HR2）-gp41（HIV-1 包膜蛋白）胞外域中的区域以及抑制六螺旋束结构形成的化合物。众所周知，HIV-1 感染步骤可作为抗 HIV-1 药物，我们对 α-螺旋 C 区 (HR2) 衍生肽进行了改造，开发了一种有效的抗 HIV-1 肽，并发现掺入了人工七肽序列 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）替换为 C-区gp41使得具有增强的α-螺旋性的重构肽表现出高抗HIV-1活性。在开发这种高效抗HIV-1肽的基础上，我们期望这种重构策略（简称X-EE）。 -XX-KK 概念），将广泛适用于使用类似于 SARS-CoV 的 Spike (S) 蛋白（Env 蛋白）的 gp41 的融合机制的其他病毒。与 gp41 类似，我们使用 X-EE-XX-KK 概念对 S 蛋白的潜在 α 螺旋序列（HR2 区域）应用相同的策略，发现设计的肽表现出很强的抗 SARS-CoV 活性。较少的

项目成果

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)

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)

Enhancement of the T140-based pharmacophores leads to the development of more potent and bio-stable CXCR4 antagonists.

• DOI: 10.1039/b306613b
• 发表时间: 2003-10
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: H. Tamamura;K. Hiramatsu;Makiko Mizumoto;S. Ueda;S. Kusano;S. Terakubo;M. Akamatsu;N. Yamamoto;J. Trent;Zixuan Wang;S. Peiper;H. Nakashima;A. Otaka;N. Fujii

Nobutaka Fujii et al.: "Molecular-size Reduction of a Potent CXCR4-chemokine Antagonist Using Orthogonal Combination of Conformation- and Sequence-based Libraries"Angew.Chem., Int.Ed.. 42. 3251-3253 (2003)

Nobutaka Fujii 等人：“使用基于构象和序列的文库的正交组合减少强效 CXCR4 趋化因子拮抗剂的分子大小”Angew.Chem.，Int.Ed.. 42. 3251-3253 (2003)

Hirokazu Tamamura et al.: "Synthesis of Potent CXCR4 Inhibitors Possessing Low Cytotoxicity and Improved Biostability Based on T140 Derivatives"Org.Biomol.Chem.. 1. 3656-3662 (2003)

Hirokazu Tamamura 等人：“基于 T140 衍生物合成具有低细胞毒性和改善生物稳定性的强效 CXCR4 抑制剂”Org.Biomol.Chem.. 1. 3656-3662 (2003)