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一种混合镜像 DNA/RNA 适体抑制胰高血糖素并在 1 型和 2 型糖尿病模型中急性改善葡萄糖耐量。

A mixed mirror-image DNA/RNA aptamer inhibits glucagon and acutely improves glucose tolerance in models of type 1 and type 2 diabetes.

机构信息

From the NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.

the Department of Animal Physiology and Biochemistry, Poznan University of Life Sciences, 35 Wolynska Street, 60637 Poznan, Poland, and.

出版信息

J Biol Chem. 2013 Jul 19;288(29):21136-21147. doi: 10.1074/jbc.M112.444414. Epub 2013 Jun 6.

DOI:10.1074/jbc.M112.444414
PMID:23744070
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3774380/
Abstract

Excessive secretion of glucagon, a functional insulin antagonist, significantly contributes to hyperglycemia in type 1 and type 2 diabetes. Accordingly, immunoneutralization of glucagon or genetic deletion of the glucagon receptor improved glucose homeostasis in animal models of diabetes. Despite this strong evidence, agents that selectively interfere with endogenous glucagon have not been implemented in clinical practice yet. We report the discovery of mirror-image DNA-aptamers (Spiegelmer®) that bind and inhibit glucagon. The affinity of the best binding DNA oligonucleotide was remarkably increased (>25-fold) by the introduction of oxygen atoms at selected 2'-positions through deoxyribo- to ribonucleotide exchanges resulting in a mixed DNA/RNA-Spiegelmer (NOX-G15) that binds glucagon with a Kd of 3 nm. NOX-G15 shows no cross-reactivity with related peptides such as glucagon-like peptide-1, glucagon-like peptide-2, gastric-inhibitory peptide, and prepro-vasoactive intestinal peptide. In vitro, NOX-G15 inhibits glucagon-stimulated cAMP production in CHO cells overexpressing the human glucagon receptor with an IC50 of 3.4 nm. A single injection of NOX-G15 ameliorated glucose excursions in intraperitoneal glucose tolerance tests in mice with streptozotocin-induced (type 1) diabetes and in a non-genetic mouse model of type 2 diabetes. In conclusion, the data suggest NOX-G15 as a therapeutic candidate with the potential to acutely attenuate hyperglycemia in type 1 and type 2 diabetes.

摘要

胰高血糖素的过度分泌是 1 型和 2 型糖尿病患者发生高血糖的一个重要原因，而该激素是胰岛素的功能性拮抗剂。因此，用免疫中和的方法抑制胰高血糖素或用基因敲除的方法去除胰高血糖素受体，均能改善糖尿病动物模型的血糖稳态。尽管有如此充分的证据，但能够选择性干预内源性胰高血糖素的药物尚未在临床实践中得到应用。我们报告了一种发现的 DNA 适体（ Spiegelmer® ），它能与胰高血糖素结合并抑制其活性。通过脱氧核糖核苷酸到核糖核苷酸的交换，在选定的 2'位引入氧原子，可极大地提高最佳结合 DNA 寡核苷酸的亲和力（>25 倍），从而产生一种混合 DNA/RNA-Spiegelmer（NOX-G15），其与胰高血糖素的 Kd 值为 3nm。NOX-G15 与相关肽如胰高血糖素样肽-1、胰高血糖素样肽-2、胃抑制肽和前血管活性肠肽没有交叉反应。在体外，NOX-G15 以 3.4nm 的 IC50 抑制过表达人胰高血糖素受体的 CHO 细胞中胰高血糖素刺激的 cAMP 产生。单次注射 NOX-G15 可改善链脲佐菌素诱导的（1 型）糖尿病小鼠和非遗传 2 型糖尿病小鼠的腹腔葡萄糖耐量试验中的血糖波动。总之，这些数据表明，NOX-G15 可能是一种治疗候选药物，具有在 1 型和 2 型糖尿病中急性减轻高血糖的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81d6/3774380/ae8d300473d3/zbc0341356140011.jpg
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