據(jù)一項新的研究披露,，一種阻斷胃饑餓激素（這是胃分泌的一種多肽）作用的治療可導(dǎo)致小鼠體重減輕及其它有益的代謝功效。Brad Barnett及其同事設(shè)計了一種能夠干擾這種特別的多肽激素的藥物,。
該激素已證明會通過不同的機制（其中包括刺激胃口）而促使哺乳動物的體重增加。研究人員知道,，胃饑餓激素是沒有活性的,，除非它攜帶了一條特別的辛酰基側(cè)鏈,，而該條側(cè)鏈是在一個叫做胃饑餓激素 O-乙酰轉(zhuǎn)移酶（或稱GOAT）的作用下被添加上去的,。因此，Barnett及其研究團隊設(shè)計了一個叫做GO-CoA-Tat的基于肽的藥物,，并將其注射到被喂食高脂飲食的小鼠的體內(nèi),。
他們觀察到，該藥物改善了小鼠的葡萄糖耐受性并減緩了小鼠體重增加的速度,；但令人感興趣的是,，該藥物看來不會減少食物的攝入，這一發(fā)現(xiàn)提示,，該藥物所影響的是代謝而非胃口,。GO-CoA-Tat需要反復(fù)地注射,，因此它不太可能被研發(fā)成為一種治療人類肥胖癥的藥物,；但這一研究確立了GOAT是一種未來藥物研發(fā)的有價值的標靶。（生物谷Bioon.com）
生物谷推薦英文摘要
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.
