2. Academic Validation
  3. Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity

Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity

  • J Med Chem. 2022 Dec 22;65(24):16510-16525. doi: 10.1021/acs.jmedchem.2c01380.
Matthew T Cifone 1 2,  YongLe He 1 2,  Rajeswari Basu 1 2,  Nan Wang 1,  Shabnam Davoodi 1 2,  Lauren A Spagnuolo 2,  Yuanyuan Si 2,  Taraneh Daryaee 2,  Craig E Stivala 3,  Stephen G Walker 4,  Peter J Tonge 1 2 5
Affiliations

Affiliations

  • 1 Center for Advanced Study of Drug Action, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 2 Department of Chemistry, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 3 Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 4 Department of Oral Biology and Pathology, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 5 Department of Radiology, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
PMID: 36459397 DOI: 10.1021/acs.jmedchem.2c01380
Abstract

The relationship between drug-target residence time and the post-antibiotic effect (PAE) provides insights into target vulnerability. To probe the vulnerability of bacterial Acetyl-CoA Carboxylase (ACC), a series of heterobivalent inhibitors were synthesized based on pyridopyrimidine 1 and moiramide B (3) which bind to the biotin carboxylase and carboxyltransferase ACC active sites, respectively. The heterobivalent compound 17, which has a linker of 50 Å, was a tight binding inhibitor of Escherichia coli ACC (Kiapp 0.2 nM) and could be displaced from ACC by a combination of both 1 and 3 but not just by 1. In agreement with the prolonged occupancy of ACC resulting from forced proximity binding, the heterobivalent inhibitors produced a PAE in E. coli of 1-4 h in contrast to 1 and 3 in combination or alone, indicating that ACC is a vulnerable target and highlighting the utility of kinetic, time-dependent effects in the drug mechanism of action.

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