Preclinical development of a potent D-peptide RSV inhibitor

有效的 D 肽 RSV 抑制剂的临床前开发

• 批准号: 9202782
• 负责人: Brett D Welch
• 金额: $ 99.23万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202782
• 关键词: 1 year old; ADME Study; Acute; Address; Adult; Affect; Affinity; Age; Animal Model; Animals; Antibodies; Antiviral Agents; Applications Grants; Award; Binding; Biological Assay; Cardiopulmonary; Cause of Death; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Child; Chimeric Proteins; Chronic; Clinic; Clinical; Clinical Trials; Cotton Rats; Coupled; Data; Development; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Elderly; Formulation; Goals; Gold; Grant; HIV; HIV-1; Healthcare Systems; Heart Diseases; Hospitalization; Human; Image; In Vitro; Individual; Infant; Infection; Investigational Drugs; Investigational New Drug Application; Lead; Life; Lower Respiratory Tract Infection; Lower respiratory tract structure; Lung diseases; Malaria; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mutagenicity Tests; Outpatients; Palivizumab; Peptide Hydrolases; Peptides; Phage Display; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Preclinical Testing; Premature Infant; Prevention; Property; Prophylactic treatment; Protein Engineering; Rattus; Recovery; Regimen; Research Design; Resistance; Resistance profile; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Ribavirin; Rodent; Safety; Seasons; Site; Small Business Innovation Research Grant; Solubility; Structure of parenchyma of lung; Supportive care; Symptoms; Technology; Therapeutic; Time; TimeLine; Toxic effect; Toxicokinetics; Toxicology; Vaccines; Viral; Virus; Virus Inhibitors; Visit; Weight; commercialization; cost; cost effective; design; drug candidate; drug discovery; effective therapy; experience; flu; high risk; high risk infant; immunogenicity; in vivo; inhibitor/antagonist; innovation; meetings; mortality; nonhuman primate; novel; older patient; patient population; peptide L; peptide drug; pre-clinical; preclinical study; prevent; prophylactic; research study; resistant strain; screening; seasonal influenza; synthetic peptide

PROJECT SUMMARY Respiratory syncytial virus (RSV) is the major cause of severe lower respiratory tract infections in children and infants, affecting an estimated 64 million people and causing up to 250,000 deaths worldwide per year (WHO). In the US, ~60,000 young children and ~175,000 adults are hospitalized annually due to RSV infection. High-risk adults (the elderly and patients with chronic heart or lung disease) experience the highest RSV-attributed mortality in the US (~14,000 deaths/year), commensurate with the mortality rates of seasonal influenza. RSV costs the US healthcare system billions of dollars annually. No vaccines or safe and effective therapeutics for RSV are available, although several products are in clinical trials. Currently, RSV treatment is mostly limited to supportive care, however, for the most acute cases in children, ribavirin, a broad-range antiviral with questionable RSV efficacy and significant safety issues, can be used. Use of Synagis (palivizumab), a monoclonal antibody that inhibits RSV infection in the lower respiratory tract, is limited to the highest-risk children. Furthermore, Synagis is very expensive ($8,000 – $16,000 for a standard course of therapy for a premature infant), and it only reduces RSV-related hospitalizations by 55%. There is an urgent need for new and more cost-effective anti-RSV prophylactics and therapies that can be applied to both children and adults. During Phase I of this award, Navigen employed an innovative strategy to identify a novel, protease- resistant D-peptide drug lead, CR32T, which targets the RSV entry machinery. Our drug discovery platform employs an enantiomeric screening technology (mirror-image phage display) coupled with protein design, to identify D-peptides that bind to a conserved and functionally critical site on the virus's F (fusion) protein. CR32T binds F with pM affinity and prevents it from completing a conformational change required for RSV to enter permissive cells. As such, it is a potent inhibitor of RSV in vitro. We have successfully validated this platform technology by identifying promising inhibitors for several viruses that share a conserved entry mechanism. Our analogous anti-HIV D-peptide, CPT31, inhibits all major circulating HIV-1 strains, possesses an extremely high barrier to resistance, and has minimal immunogenicity. CPT31 has demonstrated great potential in preclinical testing, including initial safety and efficacy studies in rodents and non-human primates. Our experience with CPT31 will facilitate rapid advancement of CR32T. In this three-year Phase II application, we will determine the breadth of CR32T against multiple primary RSV isolates (A and B strains), determine its potency in a gold standard animal model of RSV infection using both preventative and therapeutic dosing regimens, and complete IND-enabling studies. Our ultimate goal is to advance this promising drug candidate to the clinic where it will have a significant worldwide impact as a safe and effective preventative and therapeutic for RSV infection in children and adults.

项目摘要 呼吸综合病毒（RSV）是儿童严重下呼吸道感染的主要原因 和婴儿，估计有6400万人，每年在全球造成多达25万人死亡 （WHO）。在美国，由于RSV，约60,000名幼儿和约175,000名成年人每年住院 感染。高风险的成年人（老年人和慢性心脏或肺部疾病的患者）经历最高 美国的RSV归属死亡率（约14,000例），与季节的死亡率相称 影响力。 RSV每年花费美国医疗体系数十亿美元。 尽管有几种产品，但没有用于RSV的疫苗或安全有效的RSV治疗 临床试验。目前，RSV治疗大部分仅限于支持性护理，但对于最急性的情况 在儿童中，利巴韦林是一种具有可疑RSV效率和重大安全性问题的宽范围抗病毒，可以 被使用。使用Synagis（Palivizumab），一种单克隆抗体，抑制了较低的RSV感染 呼吸道仅限于最高危的儿童。此外，犹太仙境非常昂贵（$ 8,000 - 16,000美元用于预先婴儿的标准治疗方法），它只会减少与RSV有关 住院55％。迫切需要新的，更具成本效益的抗RSV预防药物和 可以应用于儿童和成人的疗法。 在该奖项的第一阶段期间，Navigen采用创新策略来确定一种新颖的蛋白酶 - 抗性D肽铅CR32T，靶向RSV进入机械。我们的药物发现平台 员工是一种对映体筛查技术（镜像噬菌体显示），加上蛋白质设计， 识别与病毒F（融合）蛋白上配置和功能上关键位点结合的D肽。 CR32T与P与PM亲和力结合，并防止其完成RSV所需的协商更改 输入允许的细胞。因此，它是体外RSV的潜在抑制剂。 我们通过确定了几个的承诺抑制剂，成功地验证了该平台技术 具有共同入境机制的病毒。我们的类似抗HIV D肽CPT31抑制了所有主要 循环HIV-1菌株具有极高的耐药性障碍，并且具有最低的免疫原性。 CPT31在临床前测试中表现出巨大的潜力，包括初始安全性和效率研究 啮齿动物和非人类隐私。我们在CPT31方面的经验将有助于CR32T的快速发展。 在此三年的II期应用中，我们将确定CR32T的宽度 RSV分离株（A和B菌株），确定其在RSV感染的黄金标准动物模型中的效力 预防性和治疗性剂量方案，以及完整的辅助研究。我们的最终目标是 将这个有前途的候选药物提升到诊所，在世界范围内将在全球范围内具有重大影响 以及儿童和成人RSV感染的有效预防和治疗。