The Chemistry of the Noncanonical Cyclic Dinucleotide 2′3′-cGAMP and Its Analogs

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.

Adopting STING agonist cyclic dinucleotides as a potential adjuvant for SARS-CoV-2 vaccine

“…The CDG analogue CDG SF was synthesized based on Jones and co-workers' one flask solution-phase strategy. [14][15][16] After a few attempts, some conditions and raw materials had been adjusted as shown in synthetic route (Scheme 1). The commercial available 2'-F guanosine phosphoramidite, D3, was adopted as the second portion to couple with deprotected guanosine D2.…”

“…The CDG SF was synthesized based on the one-flask synthesis strategy by Jones et al with some adjustments. 14 Evaluation of macrophage activation in vitro using J774A.1 cell line J774A.1 cells (mouse monocyte macrophage cell line) were cultured in DMEM (dulbecco's modified eagle medium) containing 10% fetal bovine serum (FBS) at 37℃, 5% CO 2 . After harvest, the cells were planted on 24-well culture plates with a density of 5×10 5 cells/well and cultured overnight.…”

Antivirusnaya sistema vrozhdennogo immuniteta: patogenez i lecheniye COVID-19

“…Образование 2',3'-cGAMP катализирует cGAMP-синтаза (cGAS) при обнаружении цитозольной двухцепочечной ДНК, и он функционирует в качестве эндогенного индуктора врожденного иммунитета путем непосредственного связывания и активации адапторного белка -стимулятора генов интерферона (STING). Циклический динуклеотид 2',3'-cGAMP стимулирует секрецию интерферона-β (INFβ), основного сигнального пути защиты, который не зависит от активации рецепторов врожденного иммунитета (toll-подобных рецепторов, TLR) [10]. Вирус коровьей оспы в клетках человека индуцирует синтез специфичных нуклеаз под названием «поксины», способных катализировать расщепление 3'-5'-связи, превращая циклический 2',3'-cGAMP в линейный Gp[2'-5']Ap[3'] динуклеотид.…”

Intratumoural immunotherapy: activation of nucleic acid sensing pattern recognition receptors

“…STING is activated by endogenously generated or exogenously provided synthetic cyclic dinucleotides (CDNs), leading to the production of type 1 IFNs and other inflammatory cytokines [39]. Synthetic CDN analogues [41,137] and small molecules that act as agonists of STING are available [138].…”