Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: Structural basis of their function

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00583190" target="_blank" >RIV/61388963:_____/24:00583190 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1016/j.str.2024.01.008" target="_blank" >https://doi.org/10.1016/j.str.2024.01.008</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.str.2024.01.008" target="_blank" >10.1016/j.str.2024.01.008</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: Structural basis of their function

Popis výsledku v původním jazyce

The cGAS-STING pathway is a crucial part of innate immunity, it serves to detect DNA in the cytoplasm and to defend against certain cancers, viruses, and bacteria. We designed and synthesized fluorinated carbocyclic cGAMP analogs, MD1203 and MD1202D (MDs), to enhance their stability and their affinity for STING. These compounds demonstrated exceptional activity against STING. Despite their distinct chemical modifications relative to the canonical cyclic dinucleotides (CDNs), crystallographic analysis revealed a binding mode with STING that was consistent with the canonical CDNs. Importantly, MDs were resistant to cleavage by viral poxin nucleases and MDs-bound poxin adopted an unliganded-like conformation. Moreover, MDs complexed with poxin showed a conformation distinct from cGAMP bound to poxin, closely resembling their conformation when bound to STING. In conclusion, the development of MD1203 and MD1202D showcases their potential as potent STING activators with remarkable stability against poxin-mediated degradation-a crucial characteristic for future development of antivirals.

Název v anglickém jazyce

Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: Structural basis of their function

Popis výsledku anglicky

The cGAS-STING pathway is a crucial part of innate immunity, it serves to detect DNA in the cytoplasm and to defend against certain cancers, viruses, and bacteria. We designed and synthesized fluorinated carbocyclic cGAMP analogs, MD1203 and MD1202D (MDs), to enhance their stability and their affinity for STING. These compounds demonstrated exceptional activity against STING. Despite their distinct chemical modifications relative to the canonical cyclic dinucleotides (CDNs), crystallographic analysis revealed a binding mode with STING that was consistent with the canonical CDNs. Importantly, MDs were resistant to cleavage by viral poxin nucleases and MDs-bound poxin adopted an unliganded-like conformation. Moreover, MDs complexed with poxin showed a conformation distinct from cGAMP bound to poxin, closely resembling their conformation when bound to STING. In conclusion, the development of MD1203 and MD1202D showcases their potential as potent STING activators with remarkable stability against poxin-mediated degradation-a crucial characteristic for future development of antivirals.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Structure

ISSN

0969-2126

e-ISSN

1878-4186

Svazek periodika

32

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

7

Strana od-do

433-439

Kód UT WoS článku

001224650900001

EID výsledku v databázi Scopus

2-s2.0-85186077651