Your browser doesn't support javascript.
loading
Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: Structural basis of their function.
Klima, Martin; Dejmek, Milan; Duchoslav, Vojtech; Eisenreichova, Andrea; Sala, Michal; Chalupsky, Karel; Chalupska, Dominika; Novotná, Barbora; Birkus, Gabriel; Nencka, Radim; Boura, Evzen.
Afiliação
  • Klima M; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Dejmek M; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Duchoslav V; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Eisenreichova A; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Sala M; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Chalupsky K; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Chalupska D; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Novotná B; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Birkus G; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic.
  • Nencka R; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic. Electronic address: nencka@uochb.cas.cz.
  • Boura E; Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2., 166 10 Prague 6, Czech Republic. Electronic address: boura@uochb.cas.cz.
Structure ; 32(4): 433-439.e4, 2024 Apr 04.
Article em En | MEDLINE | ID: mdl-38325369
ABSTRACT
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.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias / Nucleotídeos Cíclicos Limite: Humans Idioma: En Revista: Structure Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias / Nucleotídeos Cíclicos Limite: Humans Idioma: En Revista: Structure Ano de publicação: 2024 Tipo de documento: Article