HIV Protease Inhibitors & Glucose Transport

HIV蛋白酶抑制剂

• 批准号: 6868285
• 负责人: MIKE M MUECKLER
• 金额: $ 26.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868285
• 关键词: 3T3 cells; AIDS therapy; HIV infections; RNA interference; X ray crystallography; Xenopus oocyte; drug adverse effect; drug interactions; glucose metabolism; glucose transport; glucose transporter; human immunodeficiency virus; iatrogenic disease; indinavir; insulin sensitivity /resistance; mass spectrometry; matrix assisted laser desorption ionization; noninsulin dependent diabetes mellitus; polymerase chain reaction; protease inhibitor; protein binding; protein protein interaction; protein structure function; reverse transcriptase inhibitors; small interfering RNA

DESCRIPTION (provided by applicant): The advent of HIV protease inhibitor (PI) therapy was a major advance in the treatment of HIV infection. Combined treatment of HIV-infected patients with reverse transcriptase inhibitors and PIs (Highly Active Antiretroviral Therapy, HAART) has been shown to delay the onset of overt disease and to prolong survival. Current guidelines recommend the use of HAART for the treatment of all newly diagnosed cases of HIV infection. Unfortunately, HAART is associated with the development of numerous metabolic abnormalities, including peripheral lipodystrophy, hyperlipemia, insulin resistance, glucose intolerance, and type 2 diabetes. The reported incidence of type 2 diabetes in PI -treated patients is at least ten-fold greater than that in the general age- and sex-matched population and is particularly alarming considering the relatively young age of the patient populations and the rapidity of diabetes onset after the start of therapy. PIs have been shown to rapidly and selectively suppress the activity of Glut4, the insulin-responsive glucose transporter, an effect that contributes to the insulin resistance and increased incidence of diabetes associated with PI therapy. Additionally, PI-mediated inhibition of glucose transport into pancreatic beta cells appears to reduce glucose-stimulated insulin secretion, which most likely also contributes to the development of overt diabetes. These observations support a global hypothesis whereby the direct binding of PIs to glucose transporters leads to a constellation of biochemical perturbations that ultimately results in the PI-associated metabolic syndrome. The long-term goal of this proposal is to further explore this hypothesis and to determine the mechanism of the effect of PIs on glucose transport activity. To accomplish these goals, the following specific aims will be pursued: 1) To test the hypothesis that PIs suppress insulin-stimulated glucose transport by direct binding to Glut4. If this hypothesis is validated by crosslinking studies, the structural determinants of Glut4 interaction with PIs will be mapped by analysis of chimeric and mutant glucose transporters. 2) To test the hypothesis that PI-mediated inhibition of glucose transport directly contributes to lipodystrophy by suppressing adipogenesis and/or by enhancing adipocyte apoptosis.

描述（由申请人提供）：HIV蛋白酶抑制剂（PI）疗法的出现是治疗HIV感染的重大进步。已证明，通过逆转录酶抑制剂和PI（高度活性抗逆转录病毒疗法，HAART）的HIV感染患者联合治疗可延迟明显疾病的发作并延长生存率。 当前的指南建议将HAART用于治疗所有新诊断的HIV感染病例。 不幸的是，HAART与许多代谢异常的发展有关，包括外周脂肪营养不良，高脂血症，胰岛素抵抗，葡萄糖不耐症和2型糖尿病。 PI治疗患者中2型糖尿病的发生率至少比一般年龄和性别匹配的人群大十倍，并且考虑到患者人群相对年轻的年龄以及治疗开始后的糖尿病开始的速度，尤其令人震惊。 PI已显示出迅速，有选择地抑制GLUT4的活性，GLUT4（胰岛素反应性葡萄糖转运蛋白）有助于胰岛素抵抗和与PI治疗相关的糖尿病的发病率增加。此外，PI介导的葡萄糖转运到胰腺β细胞中的抑制似乎会减少葡萄糖刺激的胰岛素分泌，这很可能也有助于明显的糖尿病的发展。这些观察结果支持了一个全球假设，即PI与葡萄糖转运蛋白的直接结合导致生化扰动的星座，最终导致PI-IS相关代谢综合征。该提案的长期目标是进一步探讨这一假设，并确定PI对葡萄糖转运活性的影响的机制。 为了实现这些目标，将实现以下具体目标： 1）测试PIS通过直接结合与GLUT4抑制胰岛素刺激的葡萄糖转运的假设。如果通过交联研究验证了该假设，则将通过分析嵌合和突变葡萄糖转运蛋白的分析来映射GLUT4与PIS的结构决定因素。 2）测试PI介导的葡萄糖转运抑制直接通过抑制脂肪生成和/或增强脂肪细胞细胞凋亡而直接导致脂肪营养不良的假设。