Inhibition of HCV as an Opportunistic HIV Co-infection

抑制 HCV 作为机会性 HIV 合并感染

基本信息

批准号：
7690216
负责人：
JAMES C FISHBEIN
金额：
$ 33.35万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE COUNTY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-22 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690216
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Affect Alabama Anti-HIV Agents Anti-HIV Therapy Antibodies Antiviral Agents Binding Biological Biological Assay CD4 Lymphocyte Count CD4 Positive T Lymphocytes Carbon Cause of Death Cell Culture Techniques Cell Line Cell membrane Cells Cessation of life Chronic Chronic Disease Clinical Collaborations Communities District of Columbia Drug Exposure Drug effect disorder Drug resistance Effectiveness Event Exhibits Gagging Genetic Transcription HCV screening HIV HIV Integrase HIV-1 Hepatitis Hepatitis C Hepatitis C virus High Pressure Liquid Chromatography Highly Active Antiretroviral Therapy Holoenzymes Human Immune system In Vitro Incubated Individual Infection Integrase Integrase Inhibitors Interferons Investigation Joints LacZ Genes Lead Length Life Cycle Stages Light Liver Liver Cirrhosis Liver diseases Location Maryland Measures Metabolic Methods Modification Molecular Molecular Cloning Molecular Models Molecular Virology Monitor Mono-S Mutation National Institute of Allergy and Infectious Disease Nuclear Nucleosides Nucleotides Opportunistic Infections Outcome Patients Pharmaceutical Preparations Phosphorylation Polyproteins Positioning Attribute Principal Investigator Procedures Process Production Protease Inhibitor Protein Biosynthesis Proviruses Publications Quantitative Structure-Activity Relationship RNA RNA-Directed DNA Polymerase RNA-Directed RNA Polymerase Radiolabeled Recombinant Proteins Research Research Institute Resistance Reverse Transcriptase Inhibitors Reverse Transcription Ribavirin Risk Role Series Site Skeleton Specific qualifier value Staging Stress Structure Structure-Activity Relationship Survival Rate T-Lymphocyte Tail Techniques Testing Time Toxic effect Treatment Protocols Universities Variant Viral Viral Genome Viral Proteins Virus Virus Diseases Work Zidovudine analog anti-hepatitis C base combat computer program drug development fighting helicase in vitro activity in vivo inhibitor/antagonist inorganic phosphate member molecular modeling mutant novel nucleoside analog nucleoside inhibitor nucleoside triphosphatase particle pol Gene Products programs radiotracer research study sugar synthetic nucleotide tripolyphosphate vector viral RNA

项目摘要

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. .

描述（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药疗法，显着提高了艾滋病毒感染者的生存率，并已将获得性病毒转变为艾滋病病毒感染者。免疫缺陷综合症（艾滋病）变成一种可控的慢性疾病。然而，慢性艾滋病毒的致命后果是免疫系统逐渐衰弱，因为艾滋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，包括但不限于丙型肝炎病毒（HCV）引起的感染。肝炎病毒感染引起的终末期肝病现已成为艾滋病毒患者死亡的主要原因之一（>50%）。在最近一项探索艾滋病毒患者死因的研究中，大多数死者的丙肝病毒抗体检测呈阳性。在艾滋病毒机会性感染中，丙型肝炎病毒最近占据了中心舞台，并因多种原因引起了艾滋病研究界的警惕，其中包括：(a) 非常成功的 HAART 治疗对于同时感染艾滋病病毒和艾滋病病毒的艾滋病毒患者来说效果明显较差。 HCV，(b) HAART 治疗中使用的蛋白酶抑制剂对已经受到 HCV 压力的肝脏施加了显着程度的额外压力。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治疗的患者患肝病的风险更大，并且(c) HCV感染被认为会刺激HIV活性，例如，在HIV患者中发现HIV RNA水平增加和CD4+细胞计数减少。感染 HCV 的患者，以及 (d) 由于利巴韦林与逆转录酶的分子相互作用，批准的 1-干扰素和利巴韦林联合抗 HCV 疗法被证明会降低抗 HIV 疗法的效力HAART 中使用了 AZT 等抑制剂，导致后者的疗效下降。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患者的HCV合并感染。这些药物既不会加剧合并感染的临床表现，也不会降低用于治疗原发感染的疗法的功效或效果。我们在此提议推进三类新型扩环核苷 (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。虽然所有三类成员均在体外显示出有效的抗 HCV 活性，但前两类成员也被发现在体外具有双重抗 HCV 和抗 HIV 活性，且毒性很小或没有毒性。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，即I类化合物的早期事件和II类化合物的晚期事件。我们进行了一些初步的机制研究，结果表明所有三类化合物都是 HCV NTPase/解旋酶的抑制剂，而 I 类化合物也抑制 HIV 整合酶。目前正在进行阐明II类化合物的抗HIV活性机制的工作。 I 类和 II 类化合物的双重抗 HCV/HIV 作用对于在 HAART 治疗中用一种新作用机制的抑制剂替代 HCV 加重的蛋白酶抑制剂具有潜在意义，该抑制剂不会对肝脏造成不利影响。治疗同时感染 HCV 的 HIV 患者。由于人类尚无已知的 HIV 整合酶等价物，因此与臭名昭著的容易产生耐药性的蛋白酶抑制剂相比，整合酶抑制剂产生耐药性的机会也少得多。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 类抑制剂的另一个有吸引力的特征。。