Theta-defensins: Novel HIV-1 Uptake Inhibitors

Theta-防御素：新型 HIV-1 摄取抑制剂

• 批准号: 6696176
• 负责人: ROBERT IRVING LEHRER
• 金额: $ 38.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696176
• 关键词: Cercocebus; Macaca mulatta; Macaca nemestrina; aminoglycoside antibiotics; antiAIDS agent; capillary electrophoresis; cell line; defensins; drug screening /evaluation; high performance liquid chromatography; human immunodeficiency virus 1; human immunodeficiency virus 2; human subject; lymphocyte; matrix assisted laser desorption ionization; oligosaccharides; peptide chemical synthesis; simian immunodeficiency virus

Our broad objectives are: to ascertain the role of innate immunity in protecting against HIV-infection and disease progression; to explore the antiviral properties of primate theta-defensins and determine their mechanism of activity, and identify promising 0-defensin peptides for future therapeutic development. Theta-defensins are circular octadecapeptides. They are formed in vivo by the post-translational splicing of two nonapeptides, each derived from a truncated, alpha-defensin-like propeptide that is encoded by a DEFT gene. Some 7.5 to 10 million years ago, the DEFT genes of a hominid ancestor of Homo sapiens acquired a premature stop codon in Exon 2, which encodes the signal sequence. Consequently, although human cells still express theta-defensin mRNA, they no longer produce theta-defensin peptides. We synthesized three theta-defensin peptides (retrocyclins- 1, -2 and-3) that human ceils could have produced if their DEFT genes had not been silenced. Retrocyclin-2 was remarkably effective in protecting CD4-positive cells from infection by both T and Mtropic strains of HIV-1. Its wide protective spectrum encompassed the clade B isolates that cause most infections in our country and the Clade C isolates that predominate in southern Africa and India. Our preliminary data revealed that retrocyelins are lectins, and that they bind gp 120, CD4 and galactosylceramide with high affinity. The specific aims of this proposal are: a). To synthesize novel theta-defensins, including peptides based on DEFT gene sequences in non-human primates, b). To test theta-defensins and selected alpha- defensins (including human HN 1-3), against laboratory-adapted and wild-type strains of HIV-1, HIV-2, and SIV; c) To identify the sugars and oligosaccharides recognized by primate theta- and alpha-defensins and correlate this with their antiretroviral properties, and d) To determine which human lymphocytes express 0-defensin mRNA, and if arninoglycosides enable human cells to produce 0-defensin peptides. Health relatedness: 0- defensins constitute a novel class of HIV-uptake inhibitors with excellent potential for future therapeutic development. The proposed research will allow experienced investigators based at UCLA, The Yerkes Primate Center at Emory University and the CDC to build the required foundation for this development.

我们的总体目标是：确定先天免疫在保护免受HIV感染和疾病进展中的作用;探索灵长类动物θ-防御素的抗病毒特性并确定其活性机制，并鉴定有前途的β-防御素肽用于未来的治疗开发。θ-防御素是环状十八肽。它们通过两个九肽的翻译后剪接在体内形成，每个九肽衍生自由DEFT基因编码的截短的α-防御素样前肽。大约750万到1000万年前，智人的一个原始人类祖先的DEFT基因在外显子2中获得了一个过早的终止密码子，该密码子编码信号序列。因此，尽管人类细胞仍然表达θ-防御素mRNA，但它们不再产生θ-防御素肽。我们合成了三种θ-防御素肽（retrocyclins- 1，-2和-3），如果人类细胞的DEFT基因没有被沉默，人类细胞就可以产生这些肽。逆转录细胞周期蛋白-2在保护CD 4阳性细胞免受HIV-1的T和M嗜性株感染方面非常有效。其广泛的保护谱包括在我国引起大多数感染的进化枝B分离株和在南部非洲和印度占主导地位的进化枝C分离株。我们的初步数据表明，retrocyelins是凝集素，并且它们以高亲和力结合gp 120、CD 4和半乳糖神经酰胺。本提案的具体目标是：（a）。合成新的θ-防御素，包括基于非人灵长类动物中DEFT基因序列的肽，B）。为了测试θ-防御素和选定的α-防御素（包括人HN 1-3），针对HIV-1、HIV-2和SIV的实验室适应株和野生型株; c）鉴定灵长类动物θ-和α-防御素识别的糖和寡糖，并将其与它们的抗逆转录病毒性质相关联，和d）确定哪些人淋巴细胞表达β-防御素mRNA，以及氨基糖苷类是否能使人类细胞产生β-防御素肽。健康相关性：0-防御素构成了一类新型的HIV摄取抑制剂，具有未来治疗开发的良好潜力。拟议的研究将允许加州大学洛杉矶分校，埃默里大学耶基斯灵长类动物中心和疾病预防控制中心的经验丰富的研究人员为这一发展奠定必要的基础。

项目成果

Retrocyclins kill bacilli and germinating spores of Bacillus anthracis and inactivate anthrax lethal toxin.

逆转录素可杀死炭疽杆菌和正在萌发的孢子，并灭活炭疽致命毒素。

• DOI: 10.1074/jbc.m603614200
• 发表时间: 2006
• 期刊: The Journal of biological chemistry
• 作者: Wang,Wei;Mulakala,Chandrika;Ward,SabrinaC;Jung,Grace;Luong,Hai;Pham,Duy;Waring,AlanJ;Kaznessis,Yiannis;Lu,Wuyuan;Bradley,KennethA;Lehrer,RobertI
• 通讯作者: Lehrer,RobertI

Paradoxical effects of two theta-defensins on HIV type 1 infection.

两种 θ 防御素对 HIV 1 型感染的矛盾作用。

• DOI: 10.1089/aid.2006.0119
• 发表时间: 2007
• 期刊: AIDS research and human retroviruses
• 影响因子: 1.5
• 作者: Wang,Qiuwei;Wang,Wei;Zheng,Junying;Tabibian,Sina;Xie,Yiming;Song,Jun;Waring,AlanJ;Chiu,Robert;Yang,OttoO;Chen,IrvinSY;Lehrer,RobertI;Pang,Shen
• 通讯作者: Pang,Shen

Retrocyclin-2: a potent anti-HIV theta-defensin that forms a cyclic cystine ladder structural motif.

Retrocyclin-2：一种有效的抗 HIV θ 防御素，形成环状胱氨酸阶梯结构基序。

• DOI: 10.1007/978-0-387-73657-0_254
• 发表时间: 2009
• 期刊: Advances in experimental medicine and biology
• 作者: Daly,NorelleL;Chen,YiK;Rosengren,KJohan;Marx,UteC;Phillips,MartinL;Waring,AlanJ;Wang,Wei;Lehrer,RobertI;Craik,DavidJ
• 通讯作者: Craik,DavidJ