Protease-resistant D-peptide Inhibitors of Ebola Virus Entry

描述(申请人提供)：埃博拉病毒(EBOV)是一种丝状病毒，可在人类和非人类灵长类动物中引起高度致命的出血热。自1976年在非洲中部发现以来，已有16起自然人类疫情，平均死亡率为67%。目前还没有获得批准的药物来预防或治疗埃博拉感染。由于埃博拉病毒易于传播，致命性高，并能够引起广泛的恐慌，疾控中心将其定义为A类生物恐怖因子，这是他们最关注的类别。迫切需要有效的EBOV预防和/或治疗，以抗击自然暴发以及为潜在的生物恐怖袭击储备。该项目描述了一种创新战略，以确定抗击埃博拉病毒的新型D-肽候选药物。D-肽是天然L多肽的镜像，不能被酶消化，因此对于延长体内半衰期和降低免疫原性具有显著的治疗潜力。作为多肽，它们可以很容易地以高效力和高特异性(小分子抑制剂的罕见特征)破坏“无法下药的”大蛋白质/蛋白质界面。Navigen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)，以识别在病毒试图进入细胞时阻止病毒的D-肽。这一平台技术已经通过确定一种有前景的抗HIV临床前候选药物成功地得到验证，该候选药物是已知的最特异和最有效的D-肽抑制剂。Navigen的抗HIV D-肽针对HIV包膜蛋白上的一个保守区域，N-三聚体，在病毒进入过程中短暂暴露。它可以抑制所有主要的HIV-1病毒株，并且在设计上具有极高的抗药性屏障。埃博拉病毒使用高度相似的病毒进入机制，并在埃博拉病毒表面发现了类似的易受攻击的N-三聚体。这种N-三聚体将成为纳维根公司发现努力的目标。在这项为期两年的第一阶段SBIR中，Navigen公司建议识别并从结构上表征能够有效抑制埃博拉病毒的D-肽。在……里面 第二阶段，将完成抑制剂的优化，所得到的D-肽将进入体内疗效和毒性研究。 公共卫生相关性：埃博拉病毒是一种高度致命的出血热的病原体，目前还没有得到批准的治疗或预防措施。自20世纪70年代S以来，它一直是非洲许多自然疫情的罪魁祸首，作为潜在的生物恐怖因子是一个严重的危险(A类，疾控中心)。Navigen正在开发一种有效的新型埃博拉感染抑制剂，该药将满足自然患者群体未得到满足的需求，并用于应对生物恐怖袭击的库存。

DESCRIPTION (provided by applicant): Ebola virus (EboV) is a filovirus that causes a highly deadly hemorrhagic fever in humans and non-human primates. Since its discovery in central Africa in 1976, there have been 16 natural human outbreaks with an average mortality rate of 67%. There are no approved agents to prevent or treat Ebola infection. Due to Ebola's ease of dissemination, high lethality, and ability to cause widespread panic, the CDC defines it as a Category A bioterror agent, their category of highest concern. There is great need for an effective EboV preventative and/or treatment, both to combat natural outbreaks as well as for stockpiling for a potential bioterror attack. This project describes an innovative strategy to identify novel D-peptide drug candidates to combat Ebola. D-peptides, the mirror images of natural L-peptides, cannot be digested by proteases and, therefore, have significant therapeutic potential for long in vivo half-lives and reduced immunogenicity. As peptides, they can readily disrupt "undruggable" large protein/protein interfaces with high potency and specificity (a rare trait for small molecule inhibitors). Navigen's drug discovery platform employs an enantiomeric screening technology (mirror-image phage display) coupled with protein design, to identify D-peptides that stop viruses as they attempt to enter cells. This platform technology has been successfully validated by identifying a promising anti-HIV preclinical candidate, which is the most specific and potent D-peptide inhibitor known. Navigen's anti-HIV D-peptide targets a conserved region found on the HIV envelope protein, the N-trimer, which is transiently exposed during viral entry. It inhibits all major circulating HIV-1 strains and, by design, possesses an extremely high barrier to resistance. Ebola uses a highly similar mechanism of viral entry, and an analogous vulnerable N-trimer has been identified on the Ebola viral surface. This N-trimer will be the target for Navigen's discovery efforts. In this two-year Phase I SBIR, Navigen proposes to identify and structurally characterize D-peptides that potently inhibit Ebola virus. In Phase II, inhibitor optimization will be completed and the resulting D-peptide will be advanced to in vivo efficacy and toxicity studies. PUBLIC HEALTH RELEVANCE: Ebola virus is the causative agent of a highly deadly hemorrhagic fever for which there are no approved therapeutics or preventatives. It has been responsible for numerous natural outbreaks in Africa since the 1970's and is a serious risk as a potential bioterror agent (Category A, CDC). Navigen is developing a potent and novel inhibitor of Ebola infection, which will address the unmet needs of the natural patient population and for stockpiles to combat a bioterror attack.