TY - JOUR
T1 - Discovery of Small-Molecule Cyclic GMP-AMP Synthase Inhibitors
AU - Padilla-Salinas, Rosaura
AU - Sun, Lijun
AU - Anderson, Rachel
AU - Yang, Xikang
AU - Zhang, Shuting
AU - Chen, Zhijian J.
AU - Yin, Hang
N1 - Funding Information:
This work was funded by the National Key R&D Program of China (No. 2017YFA0505200), the Beijing Outstanding Young Scientist program (No. BJJWZYJH01201910003013), and the National Natural Science Foundation of China (Nos. 21572114 and 21825702). We thank Dr. K. Luger for providing biological reagents and research materials for the DNA intercalation studies and Dr. J. Rudolph for his help with conducting the DNA intercalation experiments.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/2/7
Y1 - 2020/2/7
N2 - Cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) (cGAS), a cytosolic DNA sensor, plays an important role in the type I interferon response. DNA from either invading microbes or self-origin triggers the enzymatic activity of cGAS. Aberrant activation of cGAS is associated with various autoimmune disorders. Only one selective probe exists for inhibiting cGAS in cells, while others are limited by their poor cellular activity or specificity, which underscores the urgency for discovering new cGAS inhibitors. Here, we describe the development of new small-molecule human cGAS (hcGAS) inhibitors (80 compounds synthesized) with high binding affinity in vitro and cellular activity. Our studies show CU-32 and CU-76 selectively inhibit the DNA pathway in human cells but have no effect on the RIG-I-MAVS or Toll-like receptor pathways. CU-32 and CU-76 represent a new class of hcGAS inhibitors with activity in cells and provide a new chemical scaffold for designing probes to study cGAS function and development of autoimmune therapeutics.
AB - Cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) (cGAS), a cytosolic DNA sensor, plays an important role in the type I interferon response. DNA from either invading microbes or self-origin triggers the enzymatic activity of cGAS. Aberrant activation of cGAS is associated with various autoimmune disorders. Only one selective probe exists for inhibiting cGAS in cells, while others are limited by their poor cellular activity or specificity, which underscores the urgency for discovering new cGAS inhibitors. Here, we describe the development of new small-molecule human cGAS (hcGAS) inhibitors (80 compounds synthesized) with high binding affinity in vitro and cellular activity. Our studies show CU-32 and CU-76 selectively inhibit the DNA pathway in human cells but have no effect on the RIG-I-MAVS or Toll-like receptor pathways. CU-32 and CU-76 represent a new class of hcGAS inhibitors with activity in cells and provide a new chemical scaffold for designing probes to study cGAS function and development of autoimmune therapeutics.
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U2 - 10.1021/acs.joc.9b02666
DO - 10.1021/acs.joc.9b02666
M3 - Article
C2 - 31829590
AN - SCOPUS:85078530227
SN - 0022-3263
VL - 85
SP - 1579
EP - 1600
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 3
ER -