2. Academic Validation
  3. Synthesis and evaluation of acyl-AMP phosphate isosteres as inhibitors of fungal acetyl CoA synthetase

Synthesis and evaluation of acyl-AMP phosphate isosteres as inhibitors of fungal acetyl CoA synthetase

  • Bioorg Med Chem Lett. 2025 Dec 15:129:130389. doi: 10.1016/j.bmcl.2025.130389.
Drashti G Daraji 1,  Andrew J Jezewski 2,  Katy M Alden 2,  Jonah P Propp 2,  Michael E Heene 1,  Calvin A Soldan 1,  Lijun Liu 3,  Kevin P Battaile 4,  Scott Lovell 5,  Bart L Staker 6,  Damian J Krysan 7,  Timothy J Hagen 8
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL, 60115, United States.
  • 2 Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United States.
  • 3 Protein Structure and X-ray Crystallography Laboratory, Del Shankel Structural Biology Center, University of Kansas, Lawrence, Kansas 66047, USA; Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA, 98109, USA.
  • 4 New York Structural Biology Center, Upton, New York 11973, USA.
  • 5 Protein Structure and X-ray Crystallography Laboratory, Del Shankel Structural Biology Center, University of Kansas, Lawrence, Kansas 66047, USA; Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA, 98109, USA. Electronic address: [email protected].
  • 6 Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA, 98109, USA.
  • 7 Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United States; Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, United States of America. Electronic address: [email protected].
  • 8 Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL, 60115, United States. Electronic address: [email protected].
PMID: 40885291 DOI: 10.1016/j.bmcl.2025.130389
Abstract

Acetyl-CoA synthetase (ACS) is a member of the adenylate-forming Enzymes superfamily. This enzyme plays a crucial role in cellular metabolism. While ACS Enzymes are non-essential in mammals, they are essential in some Fungal species and parasites that are pathogenic to humans. Hence, inhibition of the ACS enzyme is an emerging target for the development of novel anti-infectives. Alkyl AMP esters and acyl sulfamoyl adenosine (Acyl-AMS) are potent inhibitors of Fungal ACS Enzymes by mimicingthe acyl-AMP enzyme intermediate. Molecular docking studies were performed to facilitate the design of analogs and to explore their potential ligand-binding interactions with the ACS enzyme. A series of acyl-AMP isosteres were synthesized and screened for inhibitory activity against Fungal ACS Enzymes. Notably, Compound 14 was successfully crystallized with the Cryptococcus neoformans ACS1 enzyme, providing valuable structural insight for future inhibitor design.

Keywords

Acyl-AMP; Crystal structure; Enzyme inhibition; Fungal acetyl-CoA synthetase (ACS); Molecular docking; Phosphate isosteres; Synthesis.

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