Protease-resistant D-peptide inhibitors of RSV entry

描述（由申请方提供）：呼吸道合胞病毒（RSV）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6400万人，并导致全球160，000人死亡（WHO）。在美国，每年约有100，000名婴儿和约170，000名成人因RSV感染而住院。在美国，高风险成人（老年人和慢性心脏病或肺病患者）的RSV所致死亡率最高（约14，000例死亡/年），与季节性流感的发病率相似。RSV在美国医疗保健系统的年度成本约为20亿美元。目前，没有疫苗或疾病特异性治疗可用于对抗RSV，治疗主要限于支持性护理。对于大多数急性病例，可以使用利巴韦林，这是一种具有可疑疗效和重大安全性问题的广谱抗病毒药物，尽管它不适用于成人。只有一 目前，有一种预防性药物Synagis（Palivizumab），一种抑制RSV感染的单克隆抗体，但其使用仅限于高危婴儿。Synagis非常昂贵（一个疗程约5000美元），仅将高危婴儿的RSV相关住院率降低了55%。迫切需要可以应用于广泛患者群体的新的抗RSV药物和疗法。在这个项目中，我们将采用一种创新的策略，为严重缺乏服务的RSV患者群体鉴定新的蛋白酶抗性D肽候选药物。我们的药物发现平台采用了对映体筛选技术（镜像噬菌体展示）与蛋白质设计相结合，以识别在病毒感染时阻止病毒的D-肽。 试图进入一个细胞。我们已经通过鉴定一种有希望的抗HIV临床前候选药物成功验证了该平台技术，该药物是已知的最特异和有效的D肽抑制剂。我们的抗HIV D肽靶向HIV包膜蛋白（N-三聚体）区域上的保守口袋，该区域在病毒进入期间短暂暴露。它抑制所有主要的HIV-1病毒株，并且通过设计，具有极高的耐药性屏障。RSV使用高度相似的病毒进入机制，并且已经在RSV病毒表面上鉴定了N-三聚体上的类似易损口袋。这个口袋将是我们探索的目标。在这个为期两年的I期SBIR中，我们计划鉴定和结构表征第一代D肽RSV进入抑制剂。在第二阶段，我们将迅速应用我们在HIV发现工作中使用的所有优化技术，这将我们的HIV特异性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屏障。一旦我们完全优化了D肽RSV进入抑制剂的效力、特异性和耐药性，我们将探索其作为抗RSV治疗和预防剂的效用。 公共卫生相关性：呼吸道合胞病毒（RSV）感染每年导致美国约270，000名婴儿和高危成人住院治疗，导致20亿美元的医疗费用。没有治疗感染患者的疗法，唯一可用的预防性疗法非常昂贵，效果中等，仅限于用于高危婴儿。Navigen Pharmaceuticals正在开发一种有效的新型RSV感染抑制剂，如果成功，将解决对可应用于广泛患者人群的新型抗RSV药物和疗法的大量未满足需求。

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.