Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals.
Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals.
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DOI：
10.1097/qad.0b013e3283405c33
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发表时间：
2010-11-27
期刊：
影响因子：
--
通讯作者：
Douglas SD
中科院分区：
文献类型：
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作者：
Manak MM;Moshkoff DA;Nguyen LT;Meshki J;Tebas P;Tuluc F;Douglas SD
神经激肽-1受体(NK1R)拮抗剂干扰神经肽P物质(SP)与NK1R的结合，显示出新的抗HIV-1活性。由于NK1R拮抗剂有效地穿透血脑屏障，减少脑内的炎症反应，我们希望评估它们作为针对中枢神经系统HIV-1感染的抗HIV-1候选药物的潜力。用外周血单个核细胞(PBMC)检测一系列小分子药物的抗NK1R和抗HIV-1活性。其中最有希望的是Approant(Emend，Merck and Co.Inc.)，研究了它与其他抗逆转录病毒药物的潜在协同作用。通过检测P物质引起的细胞内钙升高来检测抗NK1R活性，通过检测暴露于HIV后的PBMC培养上清液中的p24抗原来评价抗HIV-1活性。在7天的PBMC培养中，确定使细胞内钙水平或病毒产生减少50%的药物浓度。在协同作用研究中，评估了阿普利康与每一类主要的抗HIV-1药物的联合效果。在所研究的NK1R拮抗剂中，Approant具有最高的抗HIV-1活性，并且对所有主要的HIV-1亚型具有同等的活性。APRAPANT与蛋白酶抑制剂(利托那韦和沙奎那韦)有协同作用，但不与核苷逆转录酶、非核苷逆转录酶或病毒进入抑制剂协同作用。Approant具有穿透血脑屏障的能力，其作为FDA批准的减少化疗中恶心和呕吐的药物的安全性记录，以及与其他抗HIV-1药物的协同活性，使其成为治疗HIV感染的有前途的候选药物。
Neurokinin-1 receptor (NK1R) antagonists interfere with binding of neuropeptide substance P (SP) to NK1R and exhibit novel anti-HIV-1 activities. Since NK1R antagonists effectively penetrate the blood-brain barrier to reduce the inflammatory response within the brain, we wished to evaluate their potential as anti-HIV-1 candidates for targeting HIV-1 infections of the central nervous system. A series of small molecule agents were evaluated for anti-NK1R and anti-HIV-1 activity using peripheral blood mononuclear cells (PBMC). The most promising of these, aprepitant (Emend, Merck and Co. Inc.), was investigated for potential synergies with other antiretroviral drugs. Anti-NK1R activity was tested by measuring intracellular calcium increase triggered by substance P. Anti-HIV-1 activity was evaluated by measuring p24 antigen in culture supernatants of PBMC following exposure to HIV. The concentration of drug which produced 50% reduction in intracellular calcium levels or viral production in 7-day PBMC cultures was determined. The combined effect of aprepitant with each of the major classes of anti-HIV-1 drugs was evaluated in synergy studies. Aprepitant had the highest anti-HIV-1 activity of the NK1R antagonists examined and was equally active against all major HIV-1 subtypes. Aprepitant acted synergistically with protease inhibitors (ritonavir and saquinavir), but not with nucleoside reverse transcriptase, non-nucleoside reverse transcriptase, or viral entry inhibitors. The ability of aprepitant to penetrate the blood-brain barrier, its safety record as an FDA approved drug for reducing nausea and vomiting in chemotherapy, and synergistic activity with other anti-HIV-1 drugs make it a promising candidate for treatment of HIV infection.