gamma-Modifizierte Triphosphate von Nucleosidanaloga als potentielle Virustatika und deren lipophile Prodrugs

• Antragsteller: Professor Dr. Chris Meier
• Fachliche Zuordnung: Biologische und Biomimetische Chemie ; Virologie
• Förderung: Förderung von 2017 bis 2021
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 329712853

• Erstellungsjahr: 2022

Zusammenfassung der Projektergebnisse

We developed the second generation TriPPPro-prodrugs for the intracellular delivery of NTP derivatives with efficient metabolic bypass and superior antiviral properties. TriPPPro-compounds bearing two lipophilic groups at the γ-phosphate or γ-phosphonate group, respectively, are designed to enable a successful crossing of biological barriers. The second generation TriPPPro-prodrugs (26, 30, 34, and 35) comprising a non-cleavable moiety in addition to a biodegradable prodrug moiety at the γ-phosphate or γ-phosphonate group, respectively, revealed a higher potential for use in antiviral chemotherapies than the first generation TriPPPro-prodrugs 8,9 bearing two biodegradable masking groups. We have convincingly shown that the development of this TriPPPro-strategy can make a significant contribution to the development of improved antiviral agents based on nucleoside analogues.

Projektbezogene Publikationen (Auswahl)

• Nucleoside triphosphate and nucleoside triphosphate analogue prodrugs. WO 2018100137 (A1) 2018-06-07; LU 2016-93331 2016-12-02
  Meier, C; Nack, T.; Zhao, C.
  
• Anti-HIV-active nucleoside triphosphate prodrugs. J. Med. Chem. 2020, 63, 6003-6027
  Jia, X.; Schols, D.; Meier, C.
  
• Lipophilic triphosphate prodrugs of various nucleoside analogues. J. Med. Chem. 2020, 63, 6991-7007
  Jia, X.; Schols, D.; Meier, C.
  
• Membrane permeable, bioreversibly modified prodrugs of nucleoside diphosphate-γ-phosphonates. J. Med. Chem. 2020, 63, 11990-12007
  Jia, X.; Weber, S.; Schols, D.; Meier, C.
  
• Prodrugs of γ-alkyl-modified nucleoside triphosphates: improved inhibition of HIV reverse transcriptase. Angew. Chem., Int. Ed. 2020, 59, 22063-22071
  Zhao, C. L.; Weber, S.; Schols, D.; Balzarini, J.; Meier, C.
  
• γ-Ketobenzyl-Modified nucleoside triphosphate prodrugs as potential antivirals. J. Med. Chem. 2020, 63, 13745-13761
  Nack, T.; de Oliveira, T. D.; Weber, S.; Schols, D.; Balzarini, J.; Meier, C.
  
• γ‐Non‐Symmetrically dimasked TriPPProprodrugs as potential antiviral agents against HIV. ChemMedChem 2020, 16, 499-512
  Zhao, C. L.; Jia, X.; Schols, D.; Balzarini, J.; Meier, C.
  
• Improving properties of the nucleobase analogs T-705/T-1105 as potential antiviral. Annu. Rep. Med. Chem. 2021, 57, 1-47
  Jia, X.; Ganter, B.; Meier, C.