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.

我们的广泛目标是：确定先天免疫在保护艾滋病毒感染和疾病进展方面的作用；探索灵长类动物抑制素的抗病毒特性并确定其活性机理，并确定有希望的0-防御素肽以实现未来的治疗发育。抑制抑制素是圆形八肽。它们是由两种非肽的翻译后剪接在体内形成的，每种肽是由截短的，α-防御素样的丙肽的丙肽，该抗肽是由feft基因编码的。大约7.5至1000万年前，Homo Sapiens的原始祖先的faft基因在Exon 2中获得了一个编码信号序列的过早停止密码子。因此，尽管人类细胞仍然表达抑制抑制素mRNA，但它们不再产生抑制抑制肽的肽。我们合成了三种硫乙肽肽肽（retrocyclins-1，-2和-3），即如果没有沉默的feft基因，人天花板可能会产生。 Retrocyclin-2非常有效地保护CD4阳性细胞免受HIV-1的T和Mtropic菌株的感染。它广泛的保护范围涵盖了进化枝B分离株，该物种引起了我们国家的大多数感染，以及在南部非洲和印度占主导地位的C型C菌株。我们的初步数据表明，逆转录蛋白是凝集素，它们与高亲和力结合GP 120，CD4和半乳糖酰胺。该提案的具体目的是：a）。为了合成新型抑制丁字蛋白，包括基于非人类灵长类动物中的特定基因序列的肽，b）。测试抑制抑制素并选择α-防御素（包括人HN 1-3），以针对HIV-1，HIV-2和SIV的实验室适应和野生型菌株； c）鉴定由灵长类动物抑郁症和α-防御素识别的糖和寡糖，并将其与它们的抗逆转录病毒特性相关，并确定d）确定哪些人淋巴细胞表达0-防御素mRNA，以及是否能够产生人类细胞来产生0-二甲状腺素细胞。健康相关性：0-防御素构成了一类新型的HIV摄取抑制剂，具有巨大的未来治疗性发育潜力。拟议的研究将允许在UCLA，埃默里大学的Yerkes灵长类中心和CDC的经验丰富的研究人员为这一发展建立所需的基础。

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