Environmentally Triggerable Retinoic Acid-Inducible Gene I Agonists Using Synthetic Polymer Overhangs.
Environmentally Triggerable Retinoic Acid-Inducible Gene I Agonists Using Synthetic Polymer Overhangs.
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DOI：
10.1021/acs.bioconjchem.7b00697
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发表时间：
2018-03-21
影响因子：
4.7
通讯作者：
Wilson JT
中科院分区：
文献类型：
--
作者：
Palmer CR;Jacobson ME;Fedorova O;Pyle AM;Wilson JT
Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern recognition receptor (PRR) that potently activates antiviral innate immunity upon recognition of 5’ triphosphorylated doublestranded RNA (pppRNA). Accordingly, RNA ligands of the RIG-I pathway have recently emerged as promising antiviral agents, vaccine adjuvants, and cancer immunotherapeutics. However, RIG-I is expressed constitutively in virtually all cell types, and therefore administration of RIG-I agonists causes risk for systemic inflammation and possible dose-limiting toxicities. Here, we establish proof-of-concept and initial design criteria for pppRNA prodrugs capable of activating the RIG-I pathway in response to specific environmental stimuli. We show that covalent conjugation of poly(ethylene glycol) (PEG) to the 3’ end of the complementary strand, i.e., on the same side but opposite strand as the 5’ triphosphate group, can generate a synthetic overhang that abrogates RIG-I activation. Additionally, conjugation of PEG through a cleavable linker - here, a reducible disulfide bond – allows for removal of the synthetic overhang and restoration of immunostimulatory activity. Furthermore, we demonstrate that blockade of RIG-I activation via synthetic overhangs is dependent on PEG molecular weight, with a critical molecular weight between 550 and 1000 Da required to inhibit activity. Additionally, we demonstrate that blockade of RIG-I activity is conjugation site-dependent as ligation of PEG to the opposite end of the RNA did not influence ligand activity. Collectively, this work demonstrates that conjugation of synthetic polymer overhangs to pppRNA through cleavable linkers is a viable strategy for the development of environmentally triggerable RIG-I-targeting prodrugs.
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影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
11.5
作者：
Dudek, Arkadiusz Z.;Yunis, Caria;Miller, Jeffrey S.
通讯作者：
Miller, Jeffrey S.
DOI：
10.1073/pnas.1105200108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Jewell, Christopher M.;Lopez, Sandra C. Bustamante;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.
影响因子：
3.7
作者：
Kell, Alison M.;Gale, Michael, Jr.
通讯作者：
Gale, Michael, Jr.