| Chapter title |
The Chemistry of the Noncanonical Cyclic Dinucleotide 2′3′-cGAMP and Its Analogs
|
|---|---|
| Chapter number | 43 |
| Book title |
Non-canonical Cyclic Nucleotides
|
| Published in |
Handbook of experimental pharmacology, July 2016
|
| DOI | 10.1007/164_2015_43 |
| Pubmed ID | |
| Book ISBNs |
978-3-31-952671-3, 978-3-31-952673-7
|
| Authors |
Schwede, Frank, Genieser, Hans-Gottfried, Rentsch, Andreas, Frank Schwede, Hans-Gottfried Genieser, Andreas Rentsch |
| Abstract |
The cyclic dinucleotides (CDNs) cyclic diguanosine monophosphate (c-diGMP) and cyclic diadenosine monophosphate (c-diAMP) with two canonical 3'→5' internucleotide linkages are ubiquitous second messenger molecules in bacteria, regulating a multitude of physiological processes. Recently the noncanonical CDN cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) featuring a mixed linkage, which consists of a 2'→5' and a 3'→5' internucleotide bond, has been identified as a signaling molecule in metazoan species in late 2012. 2'3'-cGAMP formation is biocatalyzed by cGAMP synthase (cGAS) upon sensing of cytosolic double-stranded DNA (dsDNA) and functions as an endogenous inducer of innate immunity by directly binding to and activating the adaptor protein stimulator of interferon genes (STING). Thereby 2'3'-cGAMP can stimulate interferon-β (INF-β) secretion, a major signaling pathway of host defense, which is independent of toll-like receptor (TLR) activation. Medicinal chemistry of 2'3'-cGAMP and development of corresponding analogs are still in their infancy, and only a handful of structurally related compounds are available to the scientific community. The aim of this chapter is to summarize synthetic approaches to prepare canonical and noncanonical endogenous CDNs including 2'3'-cGAMP. Furthermore, we will describe syntheses of 2'3'-cGAMP analogs bearing modifications, which will facilitate further studies of the emerging biological functions of 2'3'-cGAMP and to identify additional receptor proteins. Finally, we will review latest developments concerning 2'3'-cGAMP analogs with improved hydrolytic stability in cell cultures and in tissues, putatively qualifying for new therapeutic options on the basis of 2'3'-cGAMP signaling. |
X Demographics
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 13 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 5 | 38% |
| Student > Bachelor | 3 | 23% |
| Student > Ph. D. Student | 1 | 8% |
| Lecturer | 1 | 8% |
| Student > Master | 1 | 8% |
| Other | 1 | 8% |
| Unknown | 1 | 8% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 5 | 38% |
| Chemistry | 4 | 31% |
| Agricultural and Biological Sciences | 2 | 15% |
| Medicine and Dentistry | 1 | 8% |
| Unknown | 1 | 8% |