A Stereocontrolled Synthesis of a Phosphorothioate Cyclic Dinucleotide-Based STING Agonist

Abstract

We describe a stereodefined synthesis of the newly identified non-natural phosphorothioate cyclic dinucleotide (CDN) STING agonist, BMT-390025. The new route avoids the lowyielding racemic approach using P(III)-based reagents, and the stereospecific assembly of the phosphorothioate linkages are forged via the recently invented P(V)-based platform of the so-called PSI (Ψ) reagent system. This P(V) approach allows for the complete control of chirality of the P-based linkages and enabled conclusive evidence of the absolute configuration. The new approach offers robust procedures for preparing the stereodefined CDN in eight steps starting from advanced nucelosides, with late-stage direct drop isolations and telescoped steps enabling an efficient scale-up that proceeded in an overall 15% yield to produce multigram amounts of the CDN.

Loops Mediate Agonist-Induced Activation of the Stimulator of Interferon Genes Protein

“…25−28 According to the crystal structure analysis of the agonist-bound STING complex, agonist binding causes conformational changes in the CBD, including the movement of the α2 helix. 19,21,23,29 Such agonist-induced conformations of the CBD have been suggested to be associated with "active-like" states of STING. 28−31 However, the CBD is located in the center of the STING, which is far away from the proteinbinding interface of STING.…”

“…As an endogenous agonist of STING, cGAMP binds to a dimeric interface, termed cyclic dinucleotide-binding domain (CBD) . Various agonists, including the non-nucleotide ligand SR-717, have been reported to bind to the CBD to activate STING. − The CBD consists of three helices (α1, α2, and α5) and four strands (β2, β3, β4, and β6) (Figure S1). Researchers have identified the β4 residue R238 as an essential agonist binding residue within the STING complex. − According to the crystal structure analysis of the agonist-bound STING complex, agonist binding causes conformational changes in the CBD, including the movement of the α2 helix. ,,, Such agonist-induced conformations of the CBD have been suggested to be associated with “active-like” states of STING. − However, the CBD is located in the center of the STING, which is far away from the protein-binding interface of STING.…”

Orthosteric STING inhibition elucidates molecular correction of SAVI STING

“…Since the differences in M271 CH3 shifts between diABZI-i and diAZI-a1 were significant in magnitude and unobstructed by other correlations, we investigated whether this was a generalizable effect among other orthosteric STING inhibitors and agonists. We compared the STING-bound 1 H- 13 C HSQC spectra among an additional seven chemically diverse STING agonists including cGAMP 12–15 , cdG 16 , ABZI 5 , diABZI-a2 5 , MSA-2 17 , and BMS-025 18,19 (Fig. 2e) as well as THIQi.…”

Progress on the Synthesis and Activity of Cyclic Dinucleotides as Stimulator of Interferon Gene (STING) Agonists

“…两种化合物在 2',3'-cGAMP 的结构基础上进行 了化学修饰: IACS-8803 在 2',3'-CDA 的基础上进行了单 氟双硫修饰, IACS-8779 则在 2',3'-CDA 的结构基础上进 行了磷酸酯双硫取代修饰, 并将 A 碱基的一个 N 替换为 CH. 与已进入临床研究阶段的 ADU-S100 (26a)相比, 它们在体外显示出更强的激活 STING 通路的能力, 并 在 B16 黑色素瘤小鼠模型中显示出显著的系统抗肿瘤 反应.2021 年, Kempson 等[50] 使用 ψ 试剂法合成了一种新 型非天然硫代磷酸盐环状二核苷酸 BMT-390025 (117), ,2'-cGAMP 的基础上替换了 G 碱基, 将与 A 碱基相连的糖环替换为四元碳环, 并进行了双磷硫代修 饰. 路线避免了使用 P(III)试剂可能导致的外消旋, 以 及色谱分离的频繁使用, 以 15%的总收率得到了克级的 产物.…”