Novel Target and Small Molecule Lead Discovery Against Drug Resistant HIV

针对耐药性艾滋病毒的新靶点和小分子先导化合物的发现

• 批准号: 9199964
• 负责人: MICHAEL A MINK
• 金额: $ 22.43万
• 依托单位: SIRGA ADVANCED BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199964
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Animal Model; Animal Testing; Animals; Anti-HIV Agents; Antiviral Agents; Binding Sites; Biochemical; Biological Availability; Body Weight; Capsid; Cell Culture Techniques; Cells; Characteristics; Chemicals; Chemistry; Combined Modality Therapy; Data; Dedications; Development; Drug resistance; Economics; Epidemic; FDA approved; Family; Genome; Goals; HIV; HIV Infections; HIV drug resistance; HIV therapy; Human; In Vitro; Laboratories; Lead; Life; Metabolism; Multi-Drug Resistance; Mus; Mutation; Oral; Outcome; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Positioning Attribute; Property; Proteins; Public Health; RNA; Refractory; Research; Research Proposals; Resistance; Retroviridae; Reverse Transcription; Scientist; Series; Site; Small Business Innovation Research Grant; Source; Structure-Activity Relationship; Testing; Toxic effect; Transfer RNA; Viral; Viral Physiology; Viral Proteins; Virus Assembly; Virus Replication; Virus-Cell Membrane Interaction; Weight; analog; animal care; base; cytotoxicity; design; drug discovery; drug resistant virus; ds-DNA; experience; improved; inhibitor/antagonist; insight; lead series; meetings; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; particle; phase 2 study; programs; protein function; resistant strain; screening; small molecule

HIV/AIDS continues to be a major global public health issue with the threat of emerging, multi-drug resistant viral strains, and therefore it is also a very considerable economic issue. At the end of 2014 approximately 1 million people were living with HIV/AIDS in the US and 36.9 million people worldwide; 2 million became newly infected with AIDS in 2014. The epidemic continues to devastate even the US with some 50,000 new HIV infections each year. Despite modern combination therapies, HIV remains a considerable challenge and threat because of a rapid rise in multi-drug resistant strains. Resistance to one or more of the drugs in combination was inevitable. Millions of patients have strains of HIV that resist one or more of the currently available HIV therapies. To overcome HIV’s drug resistances, new validated targets and novel therapeutics are urgently needed. Sirga Advanced Biopharma (Sirga) is meeting this challenge with the discovery of small molecule drugs that interrupt an interaction between human cells and the virus - an interaction that is absolutely essential for viral replication and propagation. This particularly critical interaction is also one that Sirga scientists have investigated as being refractory to the emergence of drug resistance. Though interactions of host cell and viral proteins are the considered important targets of interaction, the interaction of the host RNA with viral proteins has not as yet been exploited as sites of intervention for new therapeutics, except by Sirga. Sirga’s initial research program has been extremely successful in identifying three families of the small molecules that specifically inhibit HIV replication including drug resistant strains, has low cell cytotoxicity and in very preliminary mouse testing indicated no-toxicity at mgs/kg body weight. In this Phase I research proposal, Sirga will develop these Hit compounds with its own derivative chemistries into promising Lead compounds for novel drug discovery. Sirga will determine the mechanism of action of the pharmacologically and structurally diverse putative drugs, and explore and optimize bioactive small molecule derivatives (Structure/Activity Relationships) with little to no cell and animal toxicity. The most promising of compounds will be assessed as antiviral agents against drug resistant strains of HIV. The goal is to develop two or three promising Hit molecules into Lead molecules for treating HIV/AIDS by disrupting a novel RNA/protein function found only in infected cells. The outcome of these Aims will be measureable. The mechanism of action of the compounds as novel inhibitors of viral assembly will be confirmed. Sirga will identify of 2 or 3 tractable Leads with convincing SAR, high in vitro potency (≤ 1 µM), and effective non-toxic concentrations in the nM range in cells and the range of mg/kg weight in animals. These criteria will be almost comparable to current FDA-approved anti-HIV drugs and will position the Company to propose Phase II research.

艾滋病毒/艾滋病仍然是一个重大的全球公共卫生问题， 病毒株，所以它也是一个非常可观的经济问题。截至2014年底，约1 在美国有100万人感染艾滋病毒/艾滋病，全世界有3690万人感染艾滋病毒/艾滋病; 2014年感染艾滋病。这种流行病继续蔓延，甚至在美国也有大约5万名新的艾滋病毒感染者 每年感染。尽管有现代联合疗法，艾滋病毒仍然是一个相当大的挑战和威胁 因为多重耐药菌株的迅速增加。对一种或多种联合药物的耐药性 是不可避免的数以百万计的患者携带的HIV病毒株能抵抗一种或多种目前可用的HIV病毒。 治疗为了克服HIV的耐药性，迫切需要新的经验证的靶标和新的治疗方法。 needed. Sirga Advanced Bioburma（Sirga）正在通过发现小分子来应对这一挑战 这种药物可以阻断人体细胞和病毒之间的相互作用， 对病毒复制和繁殖至关重要。这种特别重要的相互作用也是西尔加 科学家们已经研究了耐药性的出现。虽然互动的 宿主细胞和病毒蛋白质被认为是相互作用的重要靶点， 除了Sirga之外，病毒蛋白质还没有被开发作为新疗法的干预位点。 Sirga最初的研究计划非常成功地确定了三个小型家庭， 特异性抑制HIV复制的分子，包括耐药株，具有低细胞毒性， 非常初步的小鼠试验表明在毫克/千克体重下无毒性。在第一阶段的研究计划中， Sirga将开发这些Hit化合物及其衍生化学品，使其成为有前途的先导化合物， 新药发现Sirga将确定该药物的作用机制， 多样的推定药物，并探索和优化生物活性小分子衍生物（结构/活性 关系），几乎没有细胞和动物毒性。最有前途的化合物将被评估为 针对艾滋病毒耐药株的抗病毒药。我们的目标是培养两三个有前途的命中 分子转化为铅分子用于治疗艾滋病毒/艾滋病，通过破坏一种新的RNA/蛋白质功能， 被感染的细胞这些目标的结果将是可衡量的。化合物的作用机制为 将确认新的病毒装配抑制剂。Sirga将确定2或3个易于处理的线索， SAR、高体外效价（≤ 1 µ M）和细胞中nM范围内的有效无毒浓度， 动物的mg/kg体重范围。这些标准将几乎与目前FDA批准的抗艾滋病毒药物相当 药物，并将定位公司提出第二阶段的研究。