Drug Resistant HIV: Novel Target Validation and Small Molecule Lead Discovery

耐药性 HIV：新靶点验证和小分子先导化合物发现

• 批准号: 8603632
• 负责人: MICHAEL A MINK
• 金额: $ 23.31万
• 依托单位: SIRGA ADVANCED BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603632
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affinity; Animal Model; Back; Binding Sites; Biological Assay; Biological Models; Biology; Capital; Cell Culture Techniques; Cell Line; Cells; Cellular Assay; Characteristics; Chemicals; Chemistry; Clinical; Clinical Trials; Complex; Computer Simulation; Data; Dedications; Development; Dose; Drug resistance; Epidemic; Evaluation; Funding; Genome; HIV; HIV Infections; HIV drug resistance; HIV therapy; HIV-1; Human; In Vitro; Inhibitory Concentration 50; Intervention; Investigational Drugs; Investments; Lead; Letters; Libraries; Licensing; Life; Measures; Modification; Murine leukemia virus; Mutation; North America; Organic Chemistry; Organic Synthesis; Patient Noncompliance; Patients; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Positioning Attribute; Preparation; Private Sector; Property; Proteins; RNA; Research; Resistance; Resistance development; Rest; Retroviridae; Reverse Transcription; Series; Site; Small Business Innovation Research Grant; Specificity; Staging; Structural Biochemistry; Structure-Activity Relationship; Subfamily lentivirinae; Testing; Therapeutic; Toxic effect; Transfer RNA; Translating; Validation; Viral; Viral Physiology; Viral Proteins; Virus; Work; assay development; base; commercialization; computational chemistry; drug development; drug discovery; ds-DNA; experience; fight against; functional group; high throughput screening; improved; in vivo; indexing; meetings; mutant; new therapeutic target; novel; novel strategies; particle; pharmacophore; pre-clinical; preclinical study; prevent; public health relevance; research and development; research clinical testing; resistant strain; screening; small molecule; success; therapy resistant; tool; virology

DESCRIPTION (provided by applicant): Approximately 1.6 million people live with HIV/AIDS in North America; 34 million people worldwide. The HIV/AIDS epidemic is caused by a rapidly replicating retrovirus that undergoes multiple mutations, making it extremely challenging to successfully treat. Millions of patients have strains of HIV that resist one or more of the currenty available HIV therapies. Progress has been made in the global fight against HIV/AIDS, but the epidemic continues to devastate the US and the rest of the world with some 51,000 and 2.5 million new HIV infections each year, respectively. To overcome HIV's drug resistance, new, validated targets and novel therapeutics are urgently needed. Sirga has developed a novel approach that uniquely interferes with an interaction between human (the host) cells and HIV that is absolutely essential for viral replication and propagation. Sirga expects this approach to drastically reduce the potential for HIV to develop resistance to therapies. Using its proprietary mechanism- based screening (MBS) and HIV cellular assays, Sirga has successfully identified an initial set of bioactive hits that block HIV recruitment of human tRNA3Lys (htRNA3Lys), that primes reverse transcription-a critical step in viral replication. These nontoxic hits to cells at doses effective against HIV, provide an opportunity to discover a novel class of HIV drug. HIV's dedication to htRNA3Lys is a strong validation that htRNA3Lys and its recruitment by viral proteins are critical targets for which drug resistance may be difficult to achieve. During Phase I Sirga will focus on translating hits into validated and more-potent leads. In Aim 1, Sirga will use in silico and organic synthesis approaches to identify and select series of drug-like hits having higher affinity (kd in nM range) with htRNA3Lys as measured in our MBS assay. In Aim 2, Sirga will identify two to three tractable hit series having an optimum effective non-toxic concentration in the nM range in cellular assays. In Aim 3, the mode of action (MOA) and specificity of Sirga's leads to unambiguously target tRNA3Lys with high affinity will be confirmed. Phase I success will lead to a Phase II project focused on optimization/pre-clinical testing of the lead candidate; discussions with potential Phase III partners are under way. To supplement the Sirga R&D team's collective 107 years of expertise in RNA chemistry and early-stage drug discovery-including PI Dr. Vendeix's 13-year and consultant Dr. Agris' 40-year tenures in this field-Sirga has enlisted the support of Dr. Nelson of the UNC's Center for Aids Research (CFAR), a leading virology expert in HIV/AIDS. Also on the team is Mr. Janzen, a high-throughput screening (HTS) assay-development expert. The medicinal chemistry effort is supported by Dr. Frye, Director of UNC's Center for Integrative Chemical Biology and Drug Discovery and former GSK Worldwide Vice President of Discovery Medicinal Chemistry. Dr. Toone will be engaged in the physical organic chemistry of the small molecules. Dr. Dmitri Kireev, with his combined 20 years of industrial and academic drug-discovery experience, will support the computational approach.

描述（由申请人提供）：北美约有160万人感染艾滋病毒/艾滋病；全世界有3400万人。艾滋病毒/艾滋病的流行是由一种快速复制的逆转录病毒引起的，这种病毒会发生多次突变，这使得成功治疗艾滋病毒极具挑战性。数以百万计的患者携带的艾滋病毒毒株对目前可用的一种或多种艾滋病毒治疗方法有抗药性。全球抗击艾滋病取得了进展，但这一流行病仍在继续肆虐美国和世界其他地区，每年分别有5.1万和250万艾滋病新感染病例。为了克服艾滋病毒的耐药性，迫切需要新的、经过验证的靶点和新的治疗方法。Sirga开发了一种新颖的方法，可以独特地干扰人类（宿主）细胞与HIV之间的相互作用，而这种相互作用对于病毒的复制和繁殖是绝对必要的。Sirga希望这种方法能大大降低HIV对治疗产生耐药性的可能性。利用其专有的基于机制的筛选（MBS）和HIV细胞测定，Sirga已经成功地鉴定了一组初始的生物活性命中，这些命中可以阻止HIV招募人类tRNA3Lys (htRNA3Lys)，从而启动逆转录——病毒复制的关键步骤。这些对细胞的无毒攻击剂量对HIV有效，为发现一类新的HIV药物提供了机会。HIV对htRNA3Lys的贡献有力地验证了htRNA3Lys及其被病毒蛋白募集是难以实现耐药性的关键靶点。在第一阶段