Bisphosphorothioate analog of 2'3'-c-di-AMP

2’3’-c-di-AM(PS)2 (Rp,Rp)  is the Rp,Rp-isomer of the 2’3’ bisphosphorothioate analog of 3’3’-cyclic adenosine monophosphate (c-di-AMP).  c-di-AMP is second messenger molecule produced by bacteria with potent immunostimulant activity [1]. This cyclic dinucleotide (CDN) induces the production of type I interferons (IFNs) following its recognition by the endoplasmic reticulum-resident receptor STING (stimulator of interferon genes) and the recruitment of TBK1 (TANK-binding kinase 1) and IRF3 (interferon regulatory factor 3) [2].

2’3’-c-di-AM(PS)2 (Rp,Rp) is structurally identical to ADU-S100/MIW815, a clinically-relevant molecule developed by Aduro in collaboration with Novartis currently in clinical trials for the treatment of various cancers. This analog has a higher affinity for STING than c-di-AMP due to the presence of a 2’-5’, 3’-5’ mixed linkage, as found in endogenous human CDNs produced by cGAS (cyclic GMP-AMP (cGAMP) synthase) [3]. Furthermore, it activates all known human STING alleles as well as murine STING. In addition, this analog. 2’3’-c-di-AM(PS)2 (Rp,Rp) contains two phosphorothioate diester linkages to protect it against degradation by phosphodiesterases that are present in host cells or in the systemic circulation  [4]. The Rp, Rp dithio diastereoisomer has been found to induce higher type I IFN production compared to the Rp/Sp dithio diastereoisomers or c-di-AMP  [3]. In vivo studies have demonstrated that 2’3’-c-di-AM(PS)2 (Rp,Rp) may potently prime tumor antigen-specific CD8+ T-cell responses and overcome antigen-enforced immune tolerance in combination with PD-L1 blockade  [5].

Key Features of 2’3’-c-di-AM(PS)₂(Rp,Rp):

• Potent activator of all known human STING alleles as well as murine STING

• Structurally identical to the clinically-relevant ADU-S100/MIW815

• Sterile grade available for in vivo use

• Each lot is highly pure ( >95%) and functionally validated 

References:

1. Woodward JJ. et al., 2010. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science.328(5986):1703-5.
2. Jin L. et al., 2011. MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di- GMP. J Immunol. 187(5):2595-601.
3. Corrales L et al., 2015. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11(7):1018-30.
4. Yan H. et al., 2008. Synthesis and immunostimulatory properties of the phosphorothioate analogs of cdiGMP. Bioorg. Med. Chem. Lett. 18, 5631–5634.
5. Foote JB et al., 2017. A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice. Cancer Immunol Res. 5(6):468-479.

Specifications

Synonyms: (R,R)-(2',3')c-diAM(PS)₂, (2',3')-Rp,Rp-c-diAMPSS, ADU-S100, MIW815

Formula: C₂₀H₂₂N₁₀O₁₀P₂S₂ .2Na

Molecular weight: 734.50 g/mol

Purity: ≥ 95% by LC/MS & NMR

Solubility: 50 mg/ml in water

CAS number: 1638750-95-4

Quality control:

• Purity (≥ 95%) and structure have been validated by LC/MS and NMR

• Activation of STING has been validated by cellular assays

• The absence of bacterial contamination (lipoproteins & endotoxins) has been confirmed using HEK-Blue™ TLR2 and HEK-Blue™ TLR4 cells.

Contents

2’3’-c-di-AM(PS)₂ (Rp,Rp) is provided as a lyophilized powder and is available in two quantities:

• tlrl-nacda2r-01: 100 μg 2’3’-c-di-AM(PS)₂ (Rp,Rp) + 1.5 ml endotoxin-free water.

• tlrl-nacda2r: 500 μg 2’3’-c-di-AM(PS)₂ (Rp,Rp) + 1.5 ml endotoxin-free water.

Note: 2’3’-c-di-AM(PS)₂ (Rp,Rp) is sterile filtered prior to lyophilization.

 2’3’-c-di-AM(PS)₂ (Rp,Rp) is shipped at room temperature

 2’3’-c-di-AM(PS)₂ (Rp,Rp) should be stored at -20°C.

Details

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