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Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei

Zheng Zhang1, Sriram Jakkaraju, Joy Blain

  • 1Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL, USA.

Bioorganic & Medicinal Chemistry Letters
|October 26, 2013
PubMed

Insights

Researchers designed novel molecules targeting the essential bacterial enzyme 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). One compound showed high binding affinity, offering new strategies for infectious disease treatments.

Area of Science:

  • Microbiology
  • Biochemistry
  • Medicinal Chemistry

Background:

  • The methyl erythritol phosphate (MEP) pathway is crucial for isoprenoid biosynthesis in many bacteria and pathogens.
  • 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF) is a highly conserved and essential enzyme within the MEP pathway.
  • Targeting essential bacterial pathways like MEP offers a promising strategy for developing new anti-infective agents.

Purpose of the Study:

  • To design and synthesize novel inhibitors targeting the IspF enzyme.
  • To investigate the binding interactions of these compounds with IspF using biophysical and crystallographic methods.
  • To explore the potential of these compounds as leads for new anti-infective drug development.

Main Methods:

  • Structure-based drug design utilizing fragment-bound complexes of Burkholderia pseudomallei IspF.
  • Synthesis of a molecular series linking a cytidine moiety to various zinc pocket binders.
  • Surface plasmon resonance (SPR) for assessing binding affinity and kinetics.
  • X-ray crystallography for detailed structural analysis of compound-enzyme interactions.

Main Results:

  • A synthesized molecule demonstrated binding affinity comparable to cytidine diphosphate, a natural substrate, without metal-coordinating phosphate groups.
  • SPR analysis indicated potential differences in binding stoichiometry between IspF and the tested compounds.
  • Crystallographic data revealed significant variations in the binding mode of a synthesized compound compared to its design template.
  • The study provides new structural insights into IspF-inhibitor interactions.

Conclusions:

  • Novel IspF inhibitors with high binding affinity have been developed, offering a new avenue for targeting the MEP pathway.
  • The structural and binding data provide a foundation for further optimization of this compound series.
  • These findings contribute to the development of potential therapeutics against bacterial infections by inhibiting essential metabolic pathways.
Keywords:
Anti-infectiveFragment screeningIspFMEP pathwayNon-mevalonateSPR

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