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 呼吸道合胞病毒（RSV）是儿童严重下呼吸道感染的主要原因 和婴儿，影响估计6400万人，每年造成全球25万人死亡 （WHO）.在美国，每年约有60，000名幼儿和约175，000名成人因RSV住院 感染高风险成人（老年人和慢性心脏病或肺病患者）经历的最高 美国RSV所致死亡率（约14，000例死亡/年），与季节性 流感。RSV每年花费美国医疗保健系统数十亿美元。 没有疫苗或安全有效的RSV治疗剂，尽管有几种产品在市场上销售。 临床试验目前，RSV治疗主要限于支持性护理，然而，对于大多数急性病例， 在儿童中，利巴韦林是一种广谱抗病毒药物，其RSV疗效值得怀疑，且存在重大安全性问题， 被利用Synagis（帕利珠单抗），一种抑制下呼吸道合胞病毒感染的单克隆抗体， 仅限于高危儿童。此外，Synagis非常昂贵（8,000美元- 早产儿的标准疗程为16，000美元），它只会减少与RSV相关的 住院率55%。迫切需要新的和更具成本效益的抗RSV药物， 这些疗法可以适用于儿童和成人。 在该奖项的第一阶段，Navigen采用了一种创新的策略，以确定一种新的蛋白酶， 抗D-肽药物先导CR 32 T，其靶向RSV进入机制。我们的药物发现平台 采用对映体筛选技术（镜像噬菌体展示）结合蛋白质设计， 鉴定与病毒F（融合）蛋白上的保守和功能关键位点结合的D肽。 CR 32 T以pM亲和力结合F，并阻止其完成RSV所需的构象变化， 进入许可细胞。因此，它是体外RSV的有效抑制剂。 我们已经成功地验证了这种平台技术，通过确定几种有前途的抑制剂， 共享保守进入机制的病毒。我们的类似抗HIV D肽CPT 31抑制所有主要的 循环的HIV-1毒株具有极高的耐药性屏障，并且具有最小的免疫原性。 CPT 31在临床前测试中表现出巨大潜力，包括初步安全性和有效性研究 啮齿类动物和非人类灵长类动物。我们在CPT 31方面的经验将促进CR 32 T的快速发展。 在这个为期三年的第二阶段应用中，我们将确定CR 32 T针对多个主要 RSV分离株（A和B株），使用 预防性和治疗性给药方案，以及完整的IND启动研究。我们的最终目标是 将这种有前途的候选药物推向临床，在那里它将作为一种安全的药物在世界范围内产生重大影响。 以及对儿童和成人RSV感染的有效预防和治疗。