Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.
Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.
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DOI：
10.1126/science.1191175
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发表时间：
2010-11-05
期刊：
影响因子：
--
通讯作者：
Redinbo MR
中科院分区：
文献类型：
--
作者：
Wallace BD;Wang H;Lane KT;Scott JE;Orans J;Koo JS;Venkatesh M;Jobin C;Yeh LA;Mani S;Redinbo MR
常见结肠癌化疗药物CPT-11的剂量限制副作用是由共生细菌β-葡萄糖醛酸酶引起的严重腹泻，该酶在肠道中重新激活药物。我们试图在不杀死对人类健康至关重要的共生细菌的情况下靶向这些酶。通过高通量筛选鉴定出有效的细菌β-葡萄糖醛酸酶抑制剂，并显示对同源哺乳动物酶无影响。晶体结构确定了选择性是基于细菌β-葡萄糖醛酸酶特有的环。抑制剂对活的好氧和厌氧细菌的酶靶点非常有效，但不杀死细菌或损害哺乳动物细胞。最后，口服一种抑制剂可以保护小鼠免受cpt -11诱导的毒性。因此，可以设计药物来抑制必需微生物共生体中不需要的酶活性，以提高化疗疗效。
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11–induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.
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影响因子：
14.9
作者：
Marchler-Bauer A;Anderson JB;Chitsaz F;Derbyshire MK;DeWeese-Scott C;Fong JH;Geer LY;Geer RC;Gonzales NR;Gwadz M;He S;Hurwitz DI;Jackson JD;Ke Z;Lanczycki CJ;Liebert CA;Liu C;Lu F;Lu S;Marchler GH;Mullokandov M;Song JS;Tasneem A;Thanki N;Yamashita RA;Zhang D;Zhang N;Bryant SH
通讯作者：
Bryant SH
影响因子：
64.8
作者：
JACOBSON, RH;ZHANG, XJ;MATTHEWS, BW
通讯作者：
MATTHEWS, BW
影响因子：
3
作者：
Kurita, Akinobu;Kado, Shoichi;Yokokura, Teruo
通讯作者：
Yokokura, Teruo
影响因子：
2.6
作者：
GRILL, JP;MANGINOTDURR, C;BALLONGUE, J
通讯作者：
BALLONGUE, J
影响因子：
6.8
作者：
Redinbo, Matthew R.;Champoux, James J.;Hol, Wim G.J.
通讯作者：
Hol, Wim G.J.