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：
7908727
负责人：
JAMES C FISHBEIN
金额：
$ 33.42万
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/7908727
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 Regimen 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 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（由申请人提供）：高度活跃的抗逆转录病毒疗法（HAART）采用了在病毒生命周期的不同阶段作用的三药治疗方案，已大大提高了感染HIV感染的个体的存活率，并将获得的免疫缺陷综合征（AIDS）转化为可控制的慢性病。然而，慢性艾滋病毒病的命运结果是逐渐减弱的免疫系统，因为HIV主要感染CD4淋巴细胞，这有助于人体抗击感染。这使得患者容易受到机会性共同感染的影响，包括但不限于丙型肝炎病毒（HCV）。肝炎病毒感染引起的末期肝病现在是HIV患者的主要死亡原因之一（> 50％）。在最近的一项研究探索HIV患者死亡原因的研究中，大多数死者对HCV的抗体进行了阳性。在HIV的机会性感染中，特别是HCV最近占据了中心阶段，并且由于多种原因引起了艾滋病研究界的警报，包括（a）与HCV共同感染的HIV患者（b）在HAART治疗中使用的蛋白酶在HAART疗法中使用的蛋白酶在额外的压力上，HART患者的有效性相当大得多。这会导致HCV急剧加剧及其加速对肝硬化和死亡的进展。因此，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，在与HCV共同感染的HIV患者中发现了HIV RNA水平升高，CD4+细胞计数降低，并且（D）批准的抗HCV疗法与1-Inter-hciv and the teriiv the the teriiv the the teriiv the teriiv hiv hiv患者相关，因为该疗法的结合是因为利巴韦林与逆转录酶抑制剂（例如HAART中使用的AZT）的分子相互作用的感知分子相互作用，从而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药物来打击HIV患者的HCV共同感染。这些药物既不应加剧共同感染的临床表现，也不应降低用于治疗原始感染的治疗的疗效或有效性。我们在这里提议推进三种新型的环形膨胀核苷（REN）类似物，这些核苷（REN）表明有望进一步治疗HIV/HCV共同感染。尽管所有三个类别的成员在体外表现出有效的抗HCV活性，但前两个类别的成员也被发现在体外具有双重抗HCV和抗HIV活性，几乎没有毒性。两类化合物的抗HIV活性似乎是由于它们在病毒生命周期的两个不同阶段的抑制作用而产生，这是I类的早期事件，以及II类化合物的后期事件。我们进行了一些初步的机械研究，这些研究表明，这三个类别的化合物均为HCV NTPase/Helicase的抑制剂，而I类也抑制HIV整合酶。目前，这项工作正在阐明II类化合物的抗HIV活性机理方面正在进行。 I和II类化合物的双重抗HCV/HIV作用对HAART治疗中的HCV诱发蛋白酶抑制剂的潜在替代具有潜在的抑制剂，并具有一种新型作用机制的抑制剂，该抑制剂不会对与HCV共同感染的HIV患者产生不良影响。由于没有已知的人类艾滋病毒整合酶等效的人，因此与臭名昭著的抗耐药性蛋白酶抑制剂相比，积分酶抑制剂的耐药性的机会也要小得多。 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类抑制剂的另一个吸引人的特征。。