Preclinical development of a potent D-peptide RSV inhibitor

项目总结 呼吸道合胞病毒(RSV)是引起儿童严重下呼吸道感染的主要原因 和婴儿，估计影响到百万人，每年在全球造成多达250,000人死亡 (谁)。在美国，每年有约60,000名幼儿和约175,000名成年人因RSV而住院 感染。高危成年人(老年人和慢性心脏病或肺病患者)的患病风险最高 美国呼吸道合胞病毒导致的死亡率(约14,000人/年)，与季节性肺炎的死亡率相称 流行性感冒。RSV每年给美国医疗系统造成数十亿美元的损失。 目前还没有针对RSV的疫苗或安全有效的疗法，尽管有几种产品已经上市 临床试验。目前，呼吸道合胞病毒的治疗大多局限于支持性护理，然而，对于最严重的病例。 在儿童中，利巴韦林，一种广泛的抗病毒药物，具有可疑的RSV疗效和重大的安全性问题，可以 被利用。使用Synagis(Palivizumab)，一种抑制呼吸道合胞病毒感染的单抗 呼吸道，仅限于高危儿童。此外，Synagis非常昂贵(8000美元- 早产儿的标准疗程为16,000美元)，而且它只减少了RSV相关 住院率下降了55%。迫切需要新的、更具成本效益的抗RSV预防药物和 既适用于儿童，也适用于成人的疗法。 在该奖项的第一阶段，纳维根公司采用了一种创新的策略来鉴定一种新的蛋白酶-- 抗药性D-肽药物铅CR32T，目标是RSV进入机制。我们的药物发现平台 采用与蛋白质设计相结合的对映体筛选技术(镜像噬菌体展示)，以 识别与病毒F(融合)蛋白上的保守和功能关键部位结合的D-肽。 CR32T结合F与Pm亲和力，阻止它完成RSV所需的构象变化 输入允许单元格。因此，它在体外是一种有效的RSV抑制剂。 我们已经成功地验证了这一平台技术，确定了几种有前景的抑制剂 共享保守的进入机制的病毒。我们的类似抗HIV D肽，CPT31，抑制所有主要的 流行的HIV-1毒株具有极高的抗药性，免疫原性最低。 CPT31在临床前试验中显示出巨大的潜力，包括在 啮齿动物和非人灵长类动物。我们在CPT31方面的经验将促进CR32T的快速发展。 在这项为期三年的第二阶段应用中，我们将确定CR32T相对于多个主应用程序的广度 RSV分离株(A和B株)，在RSV感染的金标准动物模型中确定其效力 预防性和治疗性给药方案，以及完整的支持IND的研究。我们的最终目标是 将这种有希望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 对儿童和成人的RSV感染具有有效的预防和治疗作用。

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.