Activities of recombinant human bleomycin hydrolase on bleomycins and engineered analogues revealing new opportunities to overcome bleomycin-induced pulmonary toxicity

被引:13
作者
Crnovcic, Ivana [1 ]
Gan, Fei [2 ]
Yang, Dong [1 ]
Dong, Liao-Bin [1 ]
Schultz, Peter G. [2 ,3 ]
Shen, Ben [1 ,4 ,5 ]
机构
[1] Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA
[2] Calif Inst Biomed Res, La Jolla, CA 92037 USA
[3] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[4] Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA
[5] Scripps Res Inst, Nat Prod Lib Initiat, Jupiter, FL 33458 USA
关键词
Bleomycin; Bleomycin hydrolase; Engineered biosynthesis; Hybrid peptide-polyketide natural products; Pulmonary toxicity; CRYSTAL-STRUCTURE; SINGLE-STRAND; DNA; TALLYSOMYCIN; ANTIBIOTICS; EXPRESSION; PROTEASE; INSIGHTS; CLONING;
D O I
10.1016/j.bmcl.2018.04.065
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The bleomycins (BLMs) are widely used in combination therapies for the treatment of various cancers. Dose-dependent and cumulative pulmonary toxicity is the major cause of BLM-associated morbidity, limiting the broad uses of BLMs as anticancer drugs. The organ specificity of BLM-induced toxicity has been correlated with the expression of the hBLMH gene, encoding the human bleomycin hydrolase (hBLMH), which is poorly expressed in the lung. hBLMH hydrolyzes BLMs into the biologically inactive deamido BLMs, thereby protecting organs from BLM-induced toxicity. Here we report (i) expression of hBLMH and production and isolation of recombinant human bleomycin hydrolase (rhBLMH) from E. coli, (ii) structural characterization of deamido BLM A2 and B2 isolated from rhBLMH-catalyzed hydrolysis of BLM A2 and B2, and (iii) kinetic characterization of the rhBLMH-catalyzed hydrolysis of BLM A2 and B2, in comparison with five BLM analogues. rhBLMH from E. coli catalyzes rapid and efficient hydrolysis of all BLMs tested, exhibiting a superior catalytic efficiency for BLM B2. These findings reveal new opportunities to overcome BLM-induced pulmonary toxicity in chemotherapies, potentially by exploring BLM B2 as the preferred congener, engineering designer BLMs with optimized activity for rhBLMH, or co-administrating rhBLMH directly into the lung as a potential protein therapeutic. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2670 / 2674
页数:5
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