DISCOVERY OF SUICIDE PEPTIDE-INHIBITOR OF HIV-1 PROTEASE

HIV-1 蛋白酶自杀肽抑制剂的发现

• 批准号: 11672173
• 负责人: SHOJI Shozo
• 金额: $ 2.3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672173/
• 关键词: HIV-1; PROTEASE; p2gag; INHERENT SUICIDE PEPTIDE

In late years, it is reported that patient life was prolonged by the spread of HAART therapy. However, an appearance of multiple drug resistance virus complicates chemotherapy of AIDS with difficulty of compliance and adverse drug actions by the long term dosage of antiviral agent. Development of anti-HIV agents of the next generation that is overcoming problems of drug resistance is demanded, because HIV-1 immediately acquires the ability of drug resistance.HIV-1 protease generates viral structural proteins and various kinds of enzymes (protease, reverse transcriptase, integrase) from a precursor protein (Pr55^<gag>, p160^<gag-pol>). But, little is known what inhibits the proteolytic activity of HIV-1 protease after it has completed processing.We pay attention to this point and get the following study results till now.5) The synthetic p2^<gag> peptide inhibits the proteolytic activity of HIV-1 protease in vitro. Furthermore, the nonapeptide (AEAMSQVTN) derived from N-terminus of p2^<gag> peptide exhibits a potent inhibitory action of HIV-1 protease.2) p2^<gag> domain is highly conserved in various HIV-1 subtypes.3) It was determined by exclusion gel chromatography that HIV-1 protease after treatment of the synthetic p2^<gag> peptide dissociated from the active dimeric form to an inactive monomeric form.4) Actually, p2^<gag> peptide was detected in HIV-1 viral particles using MALDI TOF-MS.5) Some lead compounds were found by mimicing of p2^<gag> peptide.These results suggests that p2^<gag> peptide is found to be an inherent suicide inhibitor of HIV-1 protease and may play an important role in overcoming problems of the multiple drug-resistant form of HIV-1.

近年来，据报道，HAART治疗的推广延长了患者的生命。然而，多重耐药病毒的出现使艾滋病的化疗复杂化，难以依从性和长期剂量的抗病毒药物的不良反应。HIV-1蛋白酶从前体蛋白质（Pr 55 ^、p160^）产生病毒结构蛋白和各种酶（蛋白酶、逆转录酶、整合酶）<gag><gag-pol>。但是，在HIV-1蛋白酶加工完成后，究竟是什么抑制了它的蛋白水解活性，目前还知之甚少，我们关注这一点，并得到了以下研究结果：5）合成的p2^肽<gag>在体外抑制HIV-1蛋白酶的蛋白水解活性。p2^肽N端的九肽（AEAMSQVTN）<gag>对HIV-1蛋白酶有很强的抑制作用; 2）p2^肽结构<gag>域在HIV-1的不同亚型中高度保守; 3）用排阻凝胶色谱法测定了合成的p2^肽处理后HIV-1蛋白酶<gag>从活性二聚体形式解离为无活性单体形式; 4）实际上，<gag>用MALDI TOF-MS在HIV-1病毒颗粒中检测到了p2^肽; 5）通过模拟p2^肽发现了一些先导化合物<gag>。这些结果表明，p2^<gag>肽是HIV-1蛋白酶的固有自杀抑制剂，可能在克服HIV-1多重耐药形式的问题中发挥重要作用。

项目成果

Shogo Misumi, Akiko Kudo, Ryuji Azuma, Mitsunori Tomonaga, Kazuchika Furuishi, and Shozo Shoji: "The p2gag peptide, AEAMSQVTNTATIM, produced from HIV-1 Pr55gag was found to be a suicide inhibitor of HIV-1 protease."Biochem.Biophys.Res.Commun.. 241. 275-28

Shogo Misumi、Akiko Kudo、Ryuji Azuma、Mitsunori Tomonaga、Kazuchika Furuishi 和 Shozo Shoji：“由 HIV-1 Pr55gag 产生的 p2gag 肽 AEAMSQVTNTATIM 被发现是 HIV-1 蛋白酶的自杀抑制剂。”Biochem.Biophys。

S.Shoji,et al.: "The p2gag Peptide,AEAMSQVTNTATIM,Processed from HIV-1 Pr55gag Was Found to Be a Suicide inhibitor of HIV-1 Protease"Biochem.Biophys.Res.Commun. 241. 275-280 (1997)

S.Shoji 等人：“由 HIV-1 Pr55gag 加工而成的 p2gag 肽，AEAMSQVTNTATIM 被发现是 HIV-1 蛋白酶的自杀抑制剂”Biochem.Biophys.Res.Commun。