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Science:令小鼠消瘦的新药

2010/11/19 来源:美国科学促进会
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据一项新的研究披露,一种阻断胃饥饿激素(这是胃分泌的一种多肽)作用的治疗可导致小鼠体重减轻及其它有益的代谢功效。Brad Barnett及其同事设计了一种能够干扰这种特别的多肽激素的药物。 该激素已证明会通过不同的机制(其中包括刺激胃口)而促使哺乳动物的体重增加。研究人员知道,胃

据一项新的研究披露,一种阻断胃饥饿激素(这是胃分泌的一种多肽)作用的治疗可导致小鼠体重减轻及其它有益的代谢功效。Brad Barnett及其同事设计了一种能够干扰这种特别的多肽激素的药物。

该激素已证明会通过不同的机制(其中包括刺激胃口)而促使哺乳动物的体重增加。研究人员知道,胃饥饿激素是没有活性的,除非它携带了一条特别的辛酰基侧链,而该条侧链是在一个叫做胃饥饿激素 O-乙酰转移酶(或称GOAT)的作用下被添加上去的。因此,Barnett及其研究团队设计了一个叫做GO-CoA-Tat的基于肽的药物,并将其注射到被喂食高脂饮食的小鼠的体内。

他们观察到,该药物改善了小鼠的葡萄糖耐受性并减缓了小鼠体重增加的速度;但令人感兴趣的是,该药物看来不会减少食物的摄入,这一发现提示,该药物所影响的是代谢而非胃口。GO-CoA-Tat需要反复地注射,因此它不太可能被研发成为一种治疗人类肥胖症的药物;但这一研究确立了GOAT是一种未来药物研发的有价值的标靶。(生物谷Bioon.com)

生物谷推荐英文摘要

Science DOI: 10.1126/science.1196154

Glucose and Weight Control in Mice with a Designed Ghrelin O-Acyltransferase Inhibitor

Brad P. Barnett1,2,*, Yousang Hwang1,*, Martin S. Taylor1,2,*, Henriette Kirchner3, Paul T. Pfluger3, Vincent Bernard2, Yu-yi Lin2,6, Erin M. Bowers1, Chandrani Mukherjee1, Woo-Jin Song4, Patti A. Longo5, Daniel J. Leahy5, Mehboob A. Hussain4, Matthias H. Tsch?p3, Jef D. Boeke2,? and Philip A. Cole1,??

1Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

2Department of Molecular Biology and Genetics and High Throughput Biology Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

3Obesity Research Center, Metabolic Diseases Institute, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45237, USA.

4Metabolism Division, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

5Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

6Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser3, an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.

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