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ACS Omega. 2020 Apr 28;5(18):10401-10414. doi: 10.1021/acsomega.0c00280. eCollection 2020 May 12.
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Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy.基于组蛋白去乙酰化酶（HDACs）的双重靶向抑制剂：用于癌症治疗的新型抗肿瘤药物。
J Med Chem. 2020 Sep 10;63(17):8977-9002. doi: 10.1021/acs.jmedchem.0c00491. Epub 2020 Apr 30.
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Clin Microbiol Rev. 2018 Mar 14;31(2). doi: 10.1128/CMR.00077-17. Print 2018 Apr.
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Ir J Med Sci. 2017 Aug;186(3):733-741. doi: 10.1007/s11845-016-1538-z. Epub 2017 Jan 4.
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Transient protein-protein interactions perturb metabolome and cause gene dosage toxicity.瞬时蛋白质-蛋白质相互作用扰乱代谢组并导致基因剂量毒性。
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Tales of Dihydrofolate Binding to R67 Dihydrofolate Reductase.二氢叶酸与R67二氢叶酸还原酶结合的故事
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叶酸途径的双靶点抑制剂可抑制内在性耐甲氧苄啶的二氢叶酸还原酶DfrB。

Dual-Target Inhibitors of the Folate Pathway Inhibit Intrinsically Trimethoprim-Resistant DfrB Dihydrofolate Reductases.

作者信息

Toulouse Jacynthe L, Shi Genbin, Lemay-St-Denis Claudèle, Ebert Maximilian C C J C, Deon Daniel, Gagnon Marc, Ruediger Edward, Saint-Jacques Kévin, Forge Delphine, Vanden Eynde Jean Jacques, Marinier Anne, Ji Xinhua, Pelletier Joelle N

机构信息

Département de biochimie, Université de Montréal, Montréal, Quebec H3T 1J4, Canada.

PROTEO, Quebec G1V 0A6, Canada.

出版信息

ACS Med Chem Lett. 2020 Sep 28;11(11):2261-2267. doi: 10.1021/acsmedchemlett.0c00393. eCollection 2020 Nov 12.

DOI:10.1021/acsmedchemlett.0c00393
PMID:33214838
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7667824/
Abstract

Trimethoprim (TMP) is widely used to treat infections in humans and in livestock, accelerating the incidence of TMP resistance. The emergent and largely untracked type II dihydrofolate reductases (DfrBs) are intrinsically TMP-resistant plasmid-borne Dfrs that are structurally and evolutionarily unrelated to chromosomal Dfrs. We report kinetic characterization of the known DfrB family members. Their kinetic constants are conserved and all are poorly inhibited by TMP, consistent with TMP resistance. We investigate their inhibition with known and novel bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK). Importantly, all are inhibited by the HPPK inhibitors, making these molecules dual-target inhibitors of two folate pathway enzymes that are strictly microbial.

摘要

甲氧苄啶（TMP）被广泛用于治疗人类和家畜的感染，这加速了TMP耐药性的出现。新出现且大多未被追踪的II型二氢叶酸还原酶（DfrBs）是本质上具有TMP抗性的质粒携带型Dfrs，其在结构和进化上与染色体Dfrs无关。我们报告了已知DfrB家族成员的动力学特征。它们的动力学常数是保守的，并且所有成员都对TMP抑制作用较弱，这与TMP抗性一致。我们研究了它们被已知的和新型的6-羟甲基-7,8-二氢蝶呤焦磷酸激酶（HPPK）双底物抑制剂抑制的情况。重要的是，所有成员都被HPPK抑制剂抑制，这使得这些分子成为两种严格意义上的微生物叶酸途径酶的双靶点抑制剂。