The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy'
The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy'
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DOI：
10.1016/j.nano.2015.09.009
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发表时间：
2016-01-01
影响因子：
5.4
通讯作者：
Gendelman, Howard E.
中科院分区：
文献类型：
--
作者：
Zhang, Gang;Guo, Dongwei;Gendelman, Howard E.
在延长结晶纳米配方抗逆转录病毒疗法（nanoART）的半衰期的研究期间，作为一种免疫性神经保护剂开发的混合谱系激酶-3抑制剂URMC-099显示出促进抗病毒应答。在感染的人源化NOD/SCID/IL 2 R γ c-/-小鼠中，与URMC-099联合给药的长效利托那韦增强的阿扎那韦（nanoATV/r）纳米制剂降低了淋巴组织中的病毒载量和HIV-1感染的CD 4 + T细胞数量，超过了单独使用任何一种药物。药物效应与持续的抗逆转录病毒疗法储库相关。蛋白质组学分析表明，抗逆转录病毒反应与受影响的吞噬溶酶体储存途径有关，导致nanoATV/r在Rab-associated recycling和晚期内体中的隔离;与病毒成熟相关的位点。URMC-099与nanoATV联合给药可诱导HIV-1 p24和逆转录酶活性呈剂量依赖性降低。这种药物组合为基于细胞的病毒清除提供了独特的化学婚姻。来自临床编辑：虽然成功地对抗HIV-1感染，抗逆转录病毒疗法（nanoART）的下一个改进将是设计长效疗法，如细胞内药物库。在这份报告中，作者描述了纳米抗逆转录病毒疗法与混合谱系激酶-3抑制剂URMC-099一起使用，并表明这种组合不仅延长了药物半衰期，而且具有更好的疗效。这些发现有望在未来转化为临床环境。(C)2015作者爱思唯尔公司出版
During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral load and the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues more than either drug alone in infected humanized NOD/SCID/IL2R gamma c-/- mice. The drug effects were associated with sustained ART depots. Proteomics analyses demonstrated that the antiretroviral responses were linked to affected phagolysosomal storage pathways leading to sequestration of nanoATV/r in Rab-associated recycling and late endosomes; sites associated with viral maturation. URMC-099 administered with nanoATV induced a dose-dependent reduction in HIV-1p24 and reverse transcriptase activity. This drug combination offers a unique chemical marriage for cell-based viral clearance.From the Clinical Editor: Although successful in combating HIV-1 infection, the next improvement in antiretroviral therapy (nanoART) would be to devise long acting therapy, such as intra-cellular depots. In this report, the authors described the use of nanoformulated antiretroviral therapy given together with the mixed lineage kinase-3 inhibitor URMC-099, and showed that this combination not only prolonged drug half-life, but also had better efficacy. The findings are hoped to be translated into the clinical setting in the future. (C) 2015 The Authors. Published by Elsevier Inc.