Inhibition of HCV as an Opportunistic HIV Co-infection

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）采用三种药物治疗方案，作用于病毒生命周期的不同阶段，极大地提高了艾滋病毒感染者的存活率，并将获得性免疫缺陷综合征（艾滋病）转变为一种可控的慢性疾病。然而，慢性艾滋病的一个致命后果是免疫系统逐渐减弱，因为艾滋病病毒主要感染帮助身体抵抗感染的CD4淋巴细胞。这使得患者容易受到机会性合并感染，包括但不限于由丙型肝炎病毒（HCV）引起的感染。由肝炎病毒感染引起的终末期肝病现在是艾滋病毒感染者死亡的主要原因之一（50%）。在最近一项探讨艾滋病患者死亡原因的研究中，大多数死者的丙型肝炎病毒抗体检测呈阳性。在艾滋病毒的机会性感染中，丙型肝炎病毒最近占据了中心位置，并引起了艾滋病研究界的警惕，原因有很多，包括(a)非常成功的HAART疗法对合并丙型肝炎病毒的艾滋病毒患者的效果明显较差，(b) HAART疗法中使用的蛋白酶抑制剂对已经受到丙型肝炎病毒压力的肝脏施加了很大程度的额外压力。这导致丙型肝炎病毒急剧恶化，并加速发展为肝硬化和死亡。因此，接受HAART治疗的患者患肝脏疾病的风险更大，并且(c) HCV感染被认为会刺激HIV活性，例如，在合并HCV感染的HIV患者中发现HIV RNA水平升高和CD4+细胞计数降低。(d)已获批准的1-干扰素和利巴韦林联合抗hcv治疗被证明会降低抗hiv治疗的效力，因为利巴韦林与HAART中使用的逆转录酶抑制剂（如AZT）存在分子相互作用，导致后者的有效性降低。由于所有这些原因，迫切需要相互兼容的抗丙型肝炎病毒和抗艾滋病毒药物来对抗艾滋病毒患者的丙型肝炎病毒合并感染。这些药物不应加重合并感染的临床表现，也不应降低用于治疗原感染的疗法的疗效或有效性。我们在此提出了三种新型的环扩展核苷（REN）类似物，它们有望进一步开发用于治疗HIV/HCV合并感染的药物。虽然这三个类别的成员在体外都显示出强大的抗hcv活性，但前两个类别的成员在体外也被发现具有抗hcv和抗hiv的双重活性，几乎没有毒性。这两类化合物的抗hiv活性似乎源于它们各自在病毒生命周期的两个不同阶段的抑制作用，第一类化合物的早期事件和第二类化合物的晚期事件。我们进行了一些初步的机制研究，表明这三类化合物都是HCV NTPase/解旋酶的抑制剂，而一类化合物也抑制HIV整合酶。目前，研究II类化合物抗hiv活性的机制正在进行中。I类和II类化合物的双重抗HCV/HIV作用意味着，在HAART治疗中，一种新的作用机制的抑制剂可能会取代一种加重HCV的蛋白酶抑制剂，这种抑制剂在治疗合并HCV感染的HIV患者时不会对肝脏产生不良影响。由于没有已知的HIV整合酶的人类等价物，因此整合酶抑制剂产生耐药性的机会也远低于众所周知的容易产生耐药性的蛋白酶抑制剂。在HIV病毒生命周期的两个不同阶段的抑制是基于REN骨架的I类和II类抑制剂的另一个吸引人的特征。

DESCRIPTION (provided by applicant): The Highly Active Antiretroviral Therapy (HAART), employing a three-drug regimen acting on different stages of the viral life cycle, has dramatically increased the survival rate of the HIV-infected individuals, and has turned the Acquired Immunodeficiency Syndrome (AIDS) into a controllable chronic illness. A fateful outcome of the chronic HIV condition, however, is the progressively weakening immune system since HIV primarily infects the CD4 lymphocytes which help the body fight infections. This makes the patients vulnerable to opportunistic co-infections including, but not limited to that caused by Hepatitis C virus (HCV). The end-stage liver diseases caused by hepatitis viral infection is now one of the major causes of death (>50%) in HIV patients. In a recent study exploring the cause of death in HIV patients, a majority of the dead had tested positive for antibodies to HCV. Out of the HIV opportunistic infections, HCV in particular has lately taken the center stage, and is causing alarms in the AIDS research community for many reasons, including (a) the vastly successful HAART therapy is considerably less effective with HIV patients co-infected with HCV, (b) the protease inhibitors used in the HAART therapy exert a significant degree of extra strain on the liver that is already stressed by HCV. This results in dramatic exacerbation of HCV and its accelerated progress to liver cirrhosis and death. Thus, patients on HAART therapy are even more at risk for liver disease, and (c) the HCV infection is believed to stimulate the HIV activity, for example, the increased HIV RNA levels and decreased CD4+ cell counts were found in HIV patients co-infected with HCV, and (d) the approved anti-HCV therapy with a combination of 1-interferon and ribavirin was shown to decrease the potency of anti-HIV therapy because of the perceived molecular interaction of ribavirin with the reverse transcriptase inhibitors such as AZT used in HAART, resulting in the latter's diminished effectiveness. For all these reasons, mutually compatible anti-HCV and anti-HIV drugs are urgently needed to combat HCV co-infection in HIV patients. These drugs should neither exacerbate the clinical manifestations of the co-infection nor diminish the efficacy or effectiveness of the therapy used for treatment of the original infection. We propose here to advance three novel classes of ring-expanded nucleoside (REN) analogues that show promise of further drug development for treating HIV/HCV co-infection. While members from all three classes have shown potent anti-HCV activity in vitro, those from the first two classes, were also found to possess dual anti-HCV and anti-HIV activities in vitro, with little or no toxicity. The anti-HIV activity of the two classes of compounds appears to arise from their respective inhibitory effect at two different stages of the viral life cycle, an early event for class I and a late event for class II compounds. We have carried out some preliminary mechanistic studies which show that compounds of all three classes are inhibitors of HCV NTPase/helicase, while those of class I also inhibit HIV Integrase. The work is currently in progress on elucidating the mechanism of anti-HIV activity of class II compounds. The dual anti-HCV/HIV action of compounds of classes I and II has implications for potential replacement of an HCV-aggravating protease inhibitor in the HAART therapy with an inhibitor of a novel mechanism of action that would not cause adverse effects on the liver in treating HIV patients co-infected with HCV. As there is no known human equivalent of HIV integrase, the chances of developing drug resistance for integrase inhibitors are also far less compared with the notoriously resistance-prone protease inhibitors. Inhibition at two different stages of the HIV viral life cycle is an additional attractive feature of class I & II inhibitors based on REN skeleton. .