Protease-resistant D-peptide Inhibitors of Ebola Virus Entry

描述（由申请人提供）：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年在中非发现以来，已发生16次自然人类暴发，平均死亡率为67%。没有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，杀伤力强，能够引起广泛的恐慌，疾病预防控制中心将其定义为A类生物恐怖剂，这是他们最关注的类别。非常需要有效的EboV预防和/或治疗，以对抗自然爆发以及为潜在的生物恐怖袭击进行储备。该项目描述了一种创新的策略，以确定新的D-肽药物候选人，以打击埃博拉病毒。D-肽是天然L-肽的镜像，不能被蛋白酶消化，因此具有显著的治疗潜力，体内半衰期长，免疫原性降低。作为肽，它们可以以高效力和特异性（小分子抑制剂的罕见特性）容易地破坏“不可药物化的”大蛋白/蛋白界面。Navigen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，以识别在病毒试图进入细胞时阻止病毒的D肽。该平台技术已通过鉴定一种有前途的抗HIV临床前候选药物而得到成功验证，该药物是已知的最具特异性和有效性的D肽抑制剂。Navigen的抗HIV D肽靶向HIV包膜蛋白上的保守区域，即N-三聚体，该区域在病毒进入过程中短暂暴露。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。埃博拉病毒使用高度相似的病毒进入机制，并且在埃博拉病毒表面上已经确定了类似的脆弱N-三聚体。这种N-三聚体将成为Navigen发现工作的目标。在这个为期两年的I期SBIR中，Navigen提出鉴定和结构表征有效抑制埃博拉病毒的D肽。在 II期，将完成抑制剂优化，所得D-肽将进入体内疗效和毒性研究。

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.