Inhibition of HCV as an Opportunistic HIV Co-infection

描述(申请人提供)：高效抗逆转录病毒疗法(HAART)，在病毒生命周期的不同阶段采用三种药物方案，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症(AIDS)变成了一种可控制的慢性病。然而，慢性艾滋病毒的一个致命后果是免疫系统逐渐减弱，因为艾滋病毒主要感染帮助身体对抗感染的CD4淋巴细胞。这使得患者容易受到机会性混合感染，包括但不限于丙型肝炎病毒(丙型肝炎病毒)引起的感染。肝炎病毒感染引起的终末期肝病目前是HIV患者死亡的主要原因之一(占50%)。在最近一项探索艾滋病毒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。在艾滋病毒机会性感染中，尤其是丙型肝炎病毒最近占据了中心舞台，并在艾滋病研究界引起了警觉，原因有很多，包括(A)非常成功的HAART疗法对合并感染丙型肝炎病毒的艾滋病毒患者的疗效大大降低，(B)HAART疗法中使用的蛋白酶抑制剂对肝脏施加了严重的额外压力，而丙型肝炎病毒已经给肝脏造成了压力。这会导致丙型肝炎病毒急剧恶化，加速发展为肝硬变和死亡。因此，接受HAART治疗的患者患肝病的风险更高，以及(C)丙型肝炎病毒感染被认为可刺激艾滋病毒的活性，例如，在合并感染丙型肝炎病毒的艾滋病毒患者中，发现艾滋病毒RNA水平增加和CD4+细胞计数下降，以及(D)已批准的与1-干扰素和利巴韦林联合使用的抗丙型肝炎病毒治疗被证明降低了抗艾滋病毒治疗的效力，因为人们认为利巴韦林与在HAART中使用的逆转录酶抑制剂如AZT存在分子相互作用，导致后者的疗效减弱。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中的丙型肝炎病毒混合感染。这些药物既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效果或效果。我们在此建议开发三类新型的扩环核苷(REN)类似物，它们有望进一步开发治疗HIV/丙型肝炎病毒联合感染的药物。虽然这三个类别的成员在体外都显示出很强的抗丙型肝炎病毒活性，但前两个类别的成员在体外也被发现具有抗丙型肝炎病毒和抗艾滋病毒的双重活性，几乎没有毒性。这两类化合物的抗艾滋病毒活性似乎源于它们在病毒生命周期的两个不同阶段各自的抑制作用，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制研究，表明这三类化合物都是丙型肝炎病毒NTPase/解旋酶的抑制剂，而I类化合物也抑制HIV整合酶。这项工作目前正在进行，以阐明第二类化合物的抗艾滋病毒活性的机制。第I类和第II类化合物的双重抗丙型肝炎病毒/艾滋病作用意味着，在HAART治疗中，可能用一种不会对肝脏造成不利影响的新作用机制的抑制剂来取代HAART疗法中的丙型肝炎病毒加重蛋白酶抑制剂，以治疗感染丙型肝炎病毒的艾滋病毒患者。由于目前还没有已知的人类HIV整合酶的等价物，整合酶抑制剂产生耐药性的可能性也远远低于臭名昭著的易耐药的蛋白酶抑制剂。在HIV病毒生命周期的两个不同阶段进行抑制是基于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. .