Protease-resistant D-peptide inhibitors of RSV entry

描述(申请人提供)：呼吸道合胞病毒是儿童和婴儿严重下呼吸道感染的主要原因，估计每年影响100万人，并导致全球160,000人死亡(世卫组织)。在美国，每年约有10万名婴儿和17万名成年人因呼吸道合胞病毒感染而住院。高危成人(老年人和患有慢性心脏病或肺病的患者)的RSV致死死亡率在美国最高(约14,000人/年)，与季节性流感的死亡率相似。美国医疗系统每年感染RSV的成本约为20亿美元。目前，还没有疫苗或针对疾病的治疗方法来对抗RSV，治疗大多限于支持性护理。对于最严重的病例，可以使用利巴韦林，这是一种疗效可疑且存在重大安全问题的大范围抗病毒药物，尽管不适用于成人。只有一个 预防药物Synagis(Palivizumab)是一种可抑制RSV感染的单抗，但其使用仅限于高危婴儿。Synagis非常昂贵(一个疗程约5000美元)，只会使高危婴儿因RSV而住院的次数减少55%。迫切需要能够应用于广大患者群体的新的抗RSV预防和治疗方法。在这个项目中，我们将应用一种创新的策略，为严重缺乏服务的RSV患者群体确定新的、耐蛋白酶的D-肽候选药物。我们的药物发现平台采用了一种与蛋白质设计相结合的对映体筛选技术(镜像噬菌体展示)来识别能够阻止病毒的D-肽 尝试进入单元格。我们已经成功地验证了这一平台技术，确定了一种有前景的抗HIV临床前候选药物，它是已知的最特异和最有效的D-肽抑制剂。我们的抗HIV D-肽针对的是HIV包膜蛋白N-三聚体区域上的一个保守口袋，该区域在病毒进入过程中瞬时暴露。它可以抑制所有主要的HIV-1病毒株，并在设计上具有极高的耐药性屏障。RSV使用高度相似的病毒进入机制，在RSV病毒表面已发现N-三聚体上类似的易受攻击的口袋。这个口袋将是我们探索努力的目标。在这项为期两年的第一阶段SBIR中，我们建议鉴定和结构表征第一代D-肽RSV进入抑制剂。在第二阶段，我们将迅速应用在我们的艾滋病毒发现工作中使用的所有优化技术，这些技术将我们针对艾滋病毒的药物的效力提高了六个数量级以上，并使其具有非凡的耐药性障碍。一旦我们充分优化了我们的D-肽RSV进入抑制剂的效力、特异性和耐药性特征，我们将探索其作为抗RSV治疗和预防的有效性。 与公共卫生相关：呼吸道合胞病毒(RSV)感染每年在美国导致约27万名婴儿和高危成年人住院，导致20亿美元的医疗费用。目前还没有治疗感染患者的疗法，唯一可用的预防性疗法是非常昂贵的、适度有效的，并且仅限于用于高危婴儿。Navigen制药公司正在开发一种有效的新型RSV感染抑制剂，如果成功，它将解决对可应用于广大患者群体的新的抗RSV预防和治疗方法的巨大需求。

DESCRIPTION (provided by applicant): 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 160,000 deaths worldwide per year (WHO). Each year in the United States, ~100,000 infants and ~170,000 adults are hospitalized due to RSV infection. High-risk adults (elderly and patients with chronic heart or lung disease) experience the highest RSV-attributed mortality in the US (~14,000 deaths/year), similar to the rates of seasonal influenza. The annual cost of RSV on the US healthcare system is ~$2 billion. Currently, no vaccines or disease-specific therapeutics are available to combat RSV, and treatment is mostly limited to supportive care. For the most acute cases, ribavirin, a broad-range antiviral with questionable efficacy and significant safety issues can be used, though it is not indicated for adults. Only one preventative is available, Synagis (Palivizumab), a monoclonal antibody that inhibits RSV infection, but its use is limited to high-risk infants. Synagis is very expensive (~$5000 for a course of therapy) and reduces RSV-related hospitalizations of high-risk infants by only 55%. There is an urgent need for new anti-RSV prophylactics and therapies that can be applied to a broad patient population. In this project we will apply an innovative strategy to identify novel, protease-resistant D-peptide drug candidates for the critically underserved RSV patient population. Our drug discovery platform employs an enantiomeric screening technology (mirror-image phage display) coupled with protein design, to identify D- peptides that stop the virus as it attempts to enter a cell. We have successfully validated this platform technology by identifying a promising anti-HIV preclinical candidate, which is the most specific and potent D- peptide inhibitor known. Our anti-HIV D-peptide targets a conserved pocket found on a region of the HIV envelope protein, the N-trimer, which is transiently exposed during viral entry. It inhibits all maor circulating HIV-1 strains and, by design, possesses an extremely high barrier to resistance. RSV uses a highly similar mechanism of viral entry, and an analogous vulnerable pocket on the N-trimer has been identified on the RSV viral surface. This pocket will be the target for our discovery efforts. In this two-year Phase I SBIR, we propose to identify and structurally characterize 1st generation D-peptide RSV entry inhibitors. In Phase II we will rapidly apply all of the optimization techniques used in our HIV discovery efforts, which improved the potency of our HIV-specific drug by over six orders of magnitude and gave it an extraordinary resistance barrier. Once we have fully optimized the potency, specificity and resistance profile of our D-peptide RSV entry inhibitor, we will explore its utility as an anti-RSV therapeutic and preventative. PUBLIC HEALTH RELEVANCE: Respiratory syncytial virus (RSV) infection causes hospitalization of an estimated 270,000 infants and high-risk adults in the US each year, leading to $2 billion in medical costs. No therapies exist to treat infected patients, and the only availabe preventative therapy is very expensive, modestly effective, and limited to use in high-risk infants. Navigen Pharmaceuticals is developing a potent and novel inhibitor of RSV infection, which, if successful, will address the considerable unmet need for new anti-RSV prophylactics and therapies that can be applied to a broad patient population.