双价乙酰辅酶 A 羧化酶抑制剂：药物靶标停留时间和时间依赖性抗菌活性。
Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity.
机构信息
Center for Advanced Study of Drug Action, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
Department of Chemistry, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
出版信息
J Med Chem. 2022 Dec 22;65(24):16510-16525. doi: 10.1021/acs.jmedchem.2c01380. Epub 2022 Dec 2.
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 and moiramide B () which bind to the biotin carboxylase and carboxyltransferase ACC active sites, respectively. The heterobivalent compound , which has a linker of 50 Å, was a tight binding inhibitor of ACC ( 0.2 nM) and could be displaced from ACC by a combination of both and but not just by . In agreement with the prolonged occupancy of ACC resulting from forced proximity binding, the heterobivalent inhibitors produced a PAE in of 1-4 h in contrast to and 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.
药物靶点停留时间与抗生素后效应（PAE）之间的关系为研究靶点易损性提供了思路。为了探究细菌乙酰辅酶 A 羧化酶（ACC）的易损性，根据分别与生物素羧化酶和羧基转移酶 ACC 活性位点结合的吡啶并嘧啶[1]和莫罗米定 B[2]，设计并合成了一系列杂双价抑制剂。其中，连接子为 50 Å 的杂双价化合物[3]对 ACC 具有强结合抑制活性（Ki0.2 nM），可以同时被[1]和[2]置换，但不能仅被[1]置换。与由于强制接近结合导致 ACC 长时间占据一致，杂双价抑制剂在 1-4 小时内产生 PAE，而[1]和[2]单独或联合使用时则没有，这表明 ACC 是一个易损的靶点，并强调了动力学、时间依赖性效应在药物作用机制中的作用。
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