Simulating Mitochondrial Toxicity of Nucleoside Analogs

模拟核苷类似物的线粒体毒性

基本信息

批准号：
7230028
负责人：
DAVID C SAMUELS
金额：
$ 17.95万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2009-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The objective of this application is to develop a computational model to study mechanisms of mitochondrial toxicity of the nucleoside analogs used in HIV therapy. Highly active antiretroviral therapy (HAART) typically contains two or more nucleoside reverse transcriptase inhibitors (NRTIs). The NRTIs are analogs to the four natural nucleosides and follow the same cellular metabolic pathways as their natural nucleoside counterparts, up to incorporation of the tri-phosphate form of the NRTIs into replicating DNA strands. When an NRTI molecule is added to the replicating DNA strand replication is terminated. The NRTIs' antiviral activity occurs through this interference with viral DNA replication. Unfortunately, NRTIs can also interfere with the replication of mitochondrial DNA (mtDNA). This is suspected to be the primary mechanism behind the mitochondrial toxicity that is a serious problem with HAART. This toxicity can appear in many forms, from lactic acidosis, which is often lethal, to cardiomyopathy, peripheral neuropathies and hepatotoxicity. In this exploratory project we propose to develop a computational model of the metabolic pathways within mitochondria of both the four natural nucleosides and of two nucleoside analogs, AZT and 3TC. The computational model includes the transport of deoxynucleosides and deoxynucleotides between the mitochondrial matrix and the cell cytoplasm, the phosphorylation of the nucleosides and the polymerization of mtDNA. The results of these simulations will be compared with experiments conducted by our collaborator, and will be used to interpret these experiments.

描述（由申请人提供）：本申请的目的是开发一种计算模型来研究HIV治疗中使用的核苷类似物的线粒体毒性机制。高活性的抗逆转录病毒治疗（HAART）通常包含两个或多个核苷逆转录酶抑制剂（NRTIS）。 NRTI是对四种天然核苷的类似物，遵循与天然核苷的相同细胞代谢途径，直到将NRTI的三磷酸形式掺入复制DNA链中。当将NRTI分子添加到复制的DNA链复制中时。 NRTIS的抗病毒活性是通过这种干扰病毒DNA复制而发生的。不幸的是，NRTI还可以干扰线粒体DNA（mtDNA）的复制。怀疑这是线粒体毒性背后的主要机制，这是HAART的严重问题。这种毒性可以以多种形式出现，从通常致命的乳酸酸中毒到心肌病，周围神经病和肝毒性。在这个探索性项目中，我们建议开发四种天然核苷和两个核苷类似物AZT和3TC的线粒体内代谢途径的计算模型。计算模型包括线粒体基质和细胞质之间的脱氧核苷和脱氧核苷酸的转运，核苷的磷酸化和mtDNA的聚合。这些模拟的结果将与我们的合作者进行的实验进行比较，并将用于解释这些实验。