Design, Synthesis and Biological Evaluation of (2',5' and 3'5'-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING).

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Xin XieXiaowei Wang

Abstract

Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor transmembrane protein that plays a pivotal role in innate immune system. STING agonists, such as endogenous cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), have been used in diverse clinical research for immunogenic tumor clearance, antiviral treatments and vaccine adjuvants. CDNs containing noncanonical mixed 3'-5' and 2'-5' phosphodiester linkages show higher potency in the activation of the STING pathway. In this study, a series of 2'3'-CDNs were designed and synthesized through a modified one-pot strategy. We then established a surface plasmon resonance (SPR)-based binding assay to quantify the binding affinities of synthesized CDNs for human STING, which requested a minuscule amount of sample without any pretreatment. Using this assay, we identified compound 8d (KD = 0.038 μM), a novel CDN that showed higher binding affinity with hSTING than cGAMP (KD = 0.543 μM). Cellular assays confirmed that 8d could trigger the expression of type I IFNs and other proinflammatory cytokines more robust than cGAMP. 8d also exhibited more resistant than cGAMP to enzymatic cleavage in vitro, indicating the successful improvement in drug availability. These findings...Continue Reading

References

May 13, 2009·Proceedings of the National Academy of Sciences of the United States of America·Wenxiang SunZhengfan Jiang
Sep 21, 2011·The Journal of Experimental Medicine·Mercedes B FuertesThomas F Gajewski
Sep 21, 2011·The Journal of Experimental Medicine·Mark S DiamondRobert D Schreiber
Sep 29, 2011·Nature·Dara L BurdetteRussell E Vance
Mar 8, 2012·Science Signaling·Yasuo Tanaka, Zhijian J Chen
Apr 24, 2014·Therapeutic Advances in Vaccines·Thomas W DubenskyMeredith L Leong
Nov 27, 2015·Proceedings of the National Academy of Sciences of the United States of America·Olivier DemariaMichel Gilliet
Sep 10, 2016·Biochemical and Biophysical Research Communications·Ken TakashimaTsukasa Seya
Sep 21, 2016·Nature Immunology·Qi ChenZhijian J Chen
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Hua WangZhijian J Chen
Dec 12, 2018·Chemistry : a European Journal·Clemens Reto DialerThomas Carell
Mar 8, 2019·Nature·Conggang ZhangZhijian J Chen
Jul 8, 2020·Chembiochem : a European Journal of Chemical Biology·Katrin RosenthalStephan Lütz

❮ Previous
Next ❯

Methods Mentioned

BETA
surface plasmon resonance
enzyme-linked immunosorbent assay
surface
biosensor
chip
MDS
chips
Assay
X-ray

Software Mentioned

AMBER10
LigX

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.