一种干扰素基因刺激物激活的非核苷酸cGAMP模拟物

作者：张馨予

本期文章：《科学》：Volume 369 Issue 6506

加州理工学院生物医学研究所Luke L. Lairson研究团队取得一项新突破。他们研制了一种干扰素基因刺激物（STING）激活的非核苷酸cGAMP模拟物。该研究于2020年8月21日发表于《科学》。

从基于路径的细胞筛选中，研究组确定了一种非核苷酸的小分子STING激动剂，称为SR-717，其表现出广泛的种间和等位基因特异性。一个1.8埃的共晶结构表明，SR-717充当直接环鸟苷单磷酸一腺苷单磷酸（cGAMP）的模拟物，可诱导STING的“闭合”构象。 SR-717具有抗肿瘤活性。促进相关组织中CD8 + T的激活，天然杀伤剂和树突状细胞的激活，并促进抗原交叉引发。 SR-717还诱导了临床相关靶标的表达，包括程序性细胞死亡1配体1（PD-L1）在依赖STING的小鼠中的表达。

干扰素基因的刺激物（STING）将先天免疫力与生物学过程联系起来，从抗肿瘤免疫力到微生物组体内平衡。目前，天然环状二核苷酸（CDN）配体的代谢不稳定性限制了对STING受体激活的抗癌潜力的机制理解。

附：英文原文

Title: Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic

Author: Emily N. Chin, Chenguang Yu, Vincent F. Vartabedian, Ying Jia, Manoj Kumar, Ana M. Gamo, William Vernier, Sabrina H. Ali, Mildred Kissai, Daniel C. Lazar, Nhan Nguyen, Laura E. Pereira, Brent Benish, Ashley K. Woods, Sean B. Joseph, Alan Chu, Kristen A. Johnson, Philipp N. Sander, Francisco Martínez-Pea, Eric N. Hampton, Travis S. Young, Dennis W. Wolan, Arnab K. Chatterjee, Peter G. Schultz, H. Michael Petrassi, John R. Teijaro, Luke L. Lairson

Issue&Volume: 2020/08/21

Abstract: Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) mimetic that induces the same “closed” conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1),

DOI: 10.1126/science.abb4255

Source: https://science.sciencemag.org/content/369/6506/993

期刊信息

Science：《科学》，创刊于1880年。隶属于美国科学促进会，最新IF：41.037

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