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）采用作用于病毒生命周期不同阶段的三种药物方案，显著提高了HIV感染者的存活率，并将获得性免疫缺陷综合征（AIDS）转变为可控制的慢性疾病。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对抗感染的CD 4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）引起的合并感染。由肝炎病毒感染引起的终末期肝病是目前HIV患者死亡的主要原因之一（>50%）。在最近一项探索艾滋病患者死亡原因的研究中，大多数死者的HCV抗体检测呈阳性。在HIV机会性感染中，HCV尤其是最近占据了中心舞台，并且由于许多原因在AIDS研究界引起了警报，包括（a）非常成功的HAART疗法对于合并感染HCV的HIV患者的有效性显著降低，（B）HAART疗法中使用的蛋白酶抑制剂对已经被HCV压迫的肝脏施加了显著程度的额外压力。这导致HCV的急剧恶化及其加速进展为肝硬化和死亡。因此，接受HAART治疗的患者甚至更有患肝病的风险，和（c）HCV感染被认为刺激HIV活性，例如，在共感染HCV的HIV患者中发现HIV RNA水平增加和CD 4+细胞计数减少，和（d）经批准的用1-干扰素和利巴韦林的组合的抗HCV疗法显示出降低抗-HCV的效力。由于病毒唑与HAART中使用的逆转录酶抑制剂（如AZT）之间存在分子相互作用，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HCV和抗HIV药物来对抗HIV患者中的HCV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始感染的治疗的疗效或有效性。我们在这里提出了三种新型的扩环核苷（REN）类似物，这些类似物有望进一步开发治疗HIV/HCV合并感染的药物。虽然来自所有三类的成员都显示出有效的体外抗HCV活性，但也发现来自前两类的成员具有体外抗HCV和抗HIV双重活性，毒性很小或没有毒性。这两类化合物的抗HIV活性似乎源于它们在病毒生命周期的两个不同阶段的各自抑制作用，I类化合物的早期事件和II类化合物的晚期事件。我们已经进行了一些初步的机理研究，表明所有三类化合物都是HCV NTR/解旋酶的抑制剂，而I类化合物也抑制HIV整合酶。目前正在研究II类化合物的抗HIV活性机制。I类和II类化合物的双重抗HCV/HIV作用暗示了在HAART治疗中用新作用机制的抑制剂潜在地替代HCV加重蛋白酶抑制剂，所述新作用机制的抑制剂在治疗同时感染HCV的HIV患者中不会对肝脏造成不良影响。由于没有已知的HIV整合酶的人类等效物，与众所周知的耐药倾向蛋白酶抑制剂相比，整合酶抑制剂产生耐药性的机会也要小得多。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类抑制剂的另一个有吸引力的特征。 .

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. .