Synthesis of Novel 3’,3’‐cyclic Dinucleotide Analogues Targeting STING Protein

Abstract

The Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferons in response to sensing viral or bacterial cytosolic DNA. Cyclic dinucleotides (CDNs) are known to activate STING. Here, we describe the synthesis and biological evaluation of two new 3',3'-CDN, in which the internucleotide linkages were replaced, respectively, by a 1,2,3-triazole moiety (as more stable isosteres of phosphate linkers) and an unsaturated carbon chain (as flexibility can led to crucial binding affinity and specificity). Thus, CuAAC and macrocyclization by RCM are the two key steps.

Engineering Escherichia coli for high-yielding 2,5-Dimethylpyrazine synthesis from L-Threonine by reconstructing metabolic pathways and enhancing cofactors regeneration

“…The 1 H NMR spectra were recorded on BrukerAvance DPX 250 or BrukerAvance 400 Spec-trometers. Chemical shifts are given in ppm and are referenced to the deuterated solvent signal or to TMS as internal standard and multiplicities are reported as s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet) [ 24 ].…”

Synthesis of Original Cyclic Dinucleotide Analogues Using the Sulfo-click Reaction

“…These efforts aim to manipulate their properties, enhance their efficacy in activating the STING protein, bolster their resistance to nucleases, and facilitate their cellular internalization and bioavailability . Consequently, many CDN analogues containing nucleobase, ribose or internucleoside linkage modifications have been described and evaluated . Among these various possible structural modifications, the most crucial one is without contest the internucleoside linkage due to its negative charge which greatly influences solubility, cell permeation, and the resistance to nucleases of CDNs.…”