Ultrapotent Inhibitors of Wild-type and Multi-drug Resistant HIV

野生型和多重耐药艾滋病毒的超强抑制剂

• 批准号: 7554597
• 负责人: Stefan G Sarafianos
• 金额: $ 38.07万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554597
• 关键词: Address; Affinity; Antiviral Agents; Binding; Biochemical; Biological Assay; Cells; Characteristics; Class; DNA; Data; Deoxyadenosines; Deoxyribose; Developed Countries; Developing Countries; Development; Drug resistance; Enzymes; Excision; Generations; HIV; HIV Infections; Highly Active Antiretroviral Therapy; In Vitro; Incidence; Kinetics; Knowledge; Molecular; Multi-Drug Resistance; Mutation; Nucleosides; Patients; Pharmaceutical Preparations; Positioning Attribute; Property; Public Health; Published Comment; RNA-Directed DNA Polymerase; Refractory; Resistance; Resistance profile; Reverse Transcriptase Inhibitors; Role; Scientific Advances and Accomplishments; Surface Plasmon Resonance; Therapeutic; Toxic effect; Variant; Viral Drug Resistance; Work; base; clinically relevant; clinically significant; deoxyadenosine; design; drug resistant virus; experience; in vitro Assay; inhibitor/antagonist; innovation; non-nucleoside reverse transcriptase inhibitors; novel; nucleoside triphosphate; response; sugar; tripolyphosphate

DESCRIPTION (provided by applicant): Nucleoside reverse transcriptase inhibitors (NRTIs) are among the most potent antiretrovirals used clinically, and are often used in first-line therapy for HIV infection. However, resistance is increasingly common in HIV drug experienced patients, and there is an urgent need to identify and develop new antiretrovirals active against these resistant HIV strains. All approved NRTIs act as chain terminators because they lack a 3'OH, and it has been a long standing paradigm that the absence of the 3'OH is essential for antiviral activity. However, this feature can also impart detrimental properties to the inhibitor, such as reduced affinity for RT compared to dNTP substrates, as well as reduced intracellular conversion to the active nucleoside triphosphate. We and our collaborators have obtained data with the novel nucleoside 4'-ethynyl, 2-fluoro deoxyadenosine (4'E-2FdA) that challenge this existing paradigm. 4'E-2FdA is the most potent NRTI described to date and acts as a chain terminator despite retaining an accessible 3'OH. Our preliminary data suggest that this apparent chain termination arises from difficulty of the primer 3'-terminus to translocate following incorporation of the compound. We therefore propose that 4'E-2FdA is a Translocation-Deficient Reverse Transcriptase Inhibitor (TDRTI). We hypothesize that the presence of the 3'OH, 4'E and 2F groups contribute to the high potency and result in the novel mechanism of inhibition. We propose to conduct detailed biochemical studies to better understand how these novel NRTIs work and to determine the specific characteristics of these compounds that contribute to their pronounced antiviral potency and excellent resistance profiles. To this end we will pursue the following Specific Aims: 1. Determine the biochemical mechanism of RT inhibition by TDRTIs. 2. Determine the biochemical mechanism of TDRTI excision by RT. 3. Determine inhibition of clinically relevant NRTI-resistant RTs by TDRTIs; interactions of clinically relevant RT inhibitors with TDRTIs and toxicity of combinations. 4. Determine the mechanism of HIV resistance to TDRTIs. Addressing these aims should significantly advance scientific knowledge and be invaluable in the design of new generations of highly active innovative NRTIs. PUBLIC HEALTH RELEVANCE: This project will characterize the biochemical and molecular basis for the unprecedented efficiency of a novel class of compounds that suppress HIV viruses extremely efficiently, and by doing so, it will help develop anti- HIV therapeutics that are both less susceptible to current clinically significant resistance mutations as well as more refractory to the development of viral drug resistance.

描述（由申请人提供）：核苷逆转录酶抑制剂（NRTI）是临床上使用的最有效的抗逆转录病毒药物之一，通常用于 HIV 感染的一线治疗。然而，在经历过艾滋病毒药物治疗的患者中，耐药性越来越普遍，迫切需要识别和开发针对这些耐药性艾滋病毒株的新型抗逆转录病毒药物。所有批准的 NRTI 都充当链终止剂，因为它们缺少 3'OH，并且长期以来的一个范例是，缺少 3'OH 对于抗病毒活性至关重要。然而，这一特征也会给抑制剂带来不利的特性，例如与 dNTP 底物相比，对 RT 的亲和力降低，以及细胞内向活性核苷三磷酸的转化减少。我们和我们的合作者已经获得了新型核苷 4'-乙炔基 2-氟脱氧腺苷 (4'E-2FdA) 的数据，挑战了这一现有范式。 4'E-2FdA 是迄今为止描述的最有效的 NRTI，尽管保留了可接近的 3'OH，但仍可充当链终止剂。我们的初步数据表明，这种明显的链终止是由于掺入化合物后引物 3' 末端难以易位所致。因此，我们提出 4'E-2FdA 是一种易位缺陷型逆转录酶抑制剂 (TDRTI)。我们假设 3'OH、4'E 和 2F 基团的存在有助于提高效力并产生新的抑制机制。我们建议进行详细的生化研究，以更好地了解这些新型 NRTI 的工作原理，并确定这些化合物的具体特征，这些特征有助于其显着的抗病毒效力和优异的耐药性。为此，我们将追求以下具体目标： 1. 确定 TDRTI 抑制 RT 的生化机制。 2.通过RT确定TDRTI切除的生化机制。 3.确定TDRTI对临床相关NRTI耐药RT的抑制作用；临床相关 RT 抑制剂与 TDRTI 的相互作用以及组合的毒性。 4.确定HIV对TDRTIs的耐药机制。实现这些目标将显着推进科学知识，并且对于设计新一代高度活跃的创新性 NRTI 具有无价的价值。 公共健康相关性：该项目将描述一类新型化合物的生化和分子基础，该化合物具有前所未有的效率，可以极其有效地抑制 HIV 病毒，通过这样做，它将有助于开发抗 HIV 疗法，这些疗法不易受到当前的影响。临床上显着的耐药突变以及更难以产生病毒耐药性。