Novel Human Interferons Produced by Protein Engineering

蛋白质工程生产的新型人类干扰素

• 批准号: 7732599
• 负责人: Kathryn C. Zoon
• 金额: $ 31.1万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732599
• 关键词: Affinity; Antiviral Agents; Apoptosis; Binding; Biological; Clinical Research; Condition; Cooperative Research and Development Agreement; Development; Engineering; Evaluation; Exhibits; Genes; Guanosine Monophosphate; Helix (Snails); Human; Hybrids; In Vitro; Interferon-alpha; Interferons; Label; Laboratories; Legal patent; Link; Malignant Neoplasms; Molecular Cloning; Phase; Production; Property; Protein Engineering; Proteins; Signal Transduction Pathway; Structure; Toxic effect; Variant; Virus Diseases; Work; base; ear helix; in vivo Model; interest; novel; pre-clinical; protein expression; receptor binding; tumor

To date at least 13 functional nonallelic human IFN-α genes have been identified which produce 12 distinct proteins with more than 50 variants that exhibit a wide breadth and varied profile of biological activities (1, 31). Why so many IFN-α species exist is still unknown and is a major question of our studies. The structures of human IFN-α molecules consist of five α-helices (labeled A-E, Figure 1), which are linked by an AB loop and three shorter segments. Human IFN-α2c and IFN-α21b are evolutionarily diverse forms of the IFN-αs that exhibit unique receptor binding properties. Based on their secondary and tertiary structures, engineering constructs from these two IFNs offers the possibility of understanding more about the structure of human IFN-αs and their relationships to antiviral, immunological, and antiproliferative/ programmed cell death activities. The primary, secondary, and tertiary structures of IFN-α proteins are crucial for IFN-α binding affinity and establishment of signal transduction pathways and biological activity. This work resulted in the production of eighteen novel IFN-α molecular clones. From these, thirteen novel IFN-α proteins have been expressed and characterized for their antiviral and antiproliferative properties. The optimization of IFN-α protein expression is in progress.

迄今为止，已经确定了至少13个功能性的非平行性人IFN-α基因，这些基因产生了12种不同的蛋白质，具有50多种变体，它们表现出广泛的广度和不同生物学活性概况（1，31）。为什么存在如此多的IFN-α物种仍然未知，这是我们研究的主要问题。 人IFN-α分子的结构由五个α-螺旋组成（标记为A-E，图1），它们由AB环和三个较短的段链接。 人IFN-α2C和IFN-α21b是具有独特受体结合特性的IFN-αs的进化形式。 基于其次要结构和三级结构，这两个IFN的工程结构提供了更多关于人IFN-α的结构及其与抗病毒，免疫学和抗增殖/程序性细胞死亡活动的关系。 IFN-α蛋白的主要，次级和第三结构对于IFN-α结合亲和力以及信号转导途径和生物学活性的建立至关重要。 这项工作导致产生了18个新型IFN-α分子克隆。 从其中，已经表达了13种新型IFN-α蛋白，并以抗病毒和抗增殖特性为特征。 IFN-α蛋白表达的优化正在进行中。

项目成果

Plasma membrane biophysical properties linked to the antiproliferative effect of interferon-alpha.

质膜生物物理特性与干扰素-α的抗增殖作用有关。

• DOI: 10.1556/amicr.52.2005.3-4.12
• 发表时间: 2005
• 期刊: Acta microbiologica et immunologica Hungarica
• 影响因子: 1.5
• 作者: Balint,Elisabeth;Grimley,PhM;Gan,Yuxiang;Zoon,KathrynC;Aszalos,A
• 通讯作者: Aszalos,A

Binding Characteristics of IFN-alpha Subvariants to IFNAR2-EC and Influence of the 6-Histidine Tag.

IFN-α 亚变体与 IFNAR2-EC 的结合特征以及 6-组氨酸标签的影响。

• DOI: 10.1089/jir.2006.26.866
• 发表时间: 2006
• 期刊: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
• 作者: Schmeisser,Hana;Kontsek,Peter;Esposito,Dominic;Gillette,William;Schreiber,Gideon;Zoon,KathrynC
• 通讯作者: Zoon,KathrynC

Two interferons alpha influence each other during their interaction with the extracellular domain of human type interferon receptor subunit 2.

• DOI: 10.1021/bi7012036
• 发表时间: 2007-12
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: H. Schmeisser;I. Gorshkova;P. Brown;P. Kontsek;P. Schuck;K. Zoon