Protease-resistant D-peptide Inhibitors of Ebola Virus Entry

埃博拉病毒入侵的蛋白酶抗性 D 肽抑制剂

• 批准号: 8394365
• 负责人: Brett D Welch
• 金额: $ 30万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394365
• 关键词: Address; Affinity; Africa; Amino Acids; Animal Model; Antiviral Agents; Applications Grants; Avidity; Binding; Biochemical; Biological Assay; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Central Africa; Coupled; Crystallography; Disease Outbreaks; Ebola virus; Effectiveness; Endosomes; Filovirus; Future; HIV; HIV Entry Inhibitors; HIV envelope protein; HIV-1; Human; Image; Infection; Lead; Ligands; Link; Membrane Proteins; Mutation; National Security; Nature; Panic; Peptide Hydrolases; Peptides; Phage Display; Pharmaceutical Preparations; Phase; Prevention; Property; Proteins; Resistance; Resolution; Risk; Screening procedure; Site; Small Business Innovation Research Grant; Specificity; Structure; Supportive care; Surface; Surface Plasmon Resonance; Technology; Testing; Therapeutic; Toxic effect; Viral; Viral Hemorrhagic Fevers; Virus; base; combat; cytotoxicity; design; drug candidate; drug discovery; immunogenicity; improved; in vivo; inhibitor/antagonist; innovation; mortality; nonhuman primate; novel; patient population; peptide L; pre-clinical; prevent; protein aminoacid sequence; small molecule; trait; transmission process

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.

描述（由申请人提供）：埃博拉病毒（EboV）是一种线状病毒，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年在非洲中部发现该病毒以来，已发生了16次人类自然暴发，平均死亡率为67%。目前还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，致死率高，并能引起广泛恐慌，美国疾病控制与预防中心将其定义为a类生物恐怖制剂，这是他们最关注的一类。我们非常需要一种有效的埃博拉病毒预防和/或治疗方法，既要对抗自然暴发，也要为潜在的生物恐怖袭击进行储存。该项目描述了一种创新策略，以确定对抗埃博拉病毒的新型d肽候选药物。d肽是天然l肽的镜像，不能被蛋白酶消化，因此具有较长的体内半衰期和较低的免疫原性的显著治疗潜力。作为多肽，它们可以很容易地以高效率和特异性破坏“不可药物”的大蛋白质/蛋白质界面（小分子抑制剂的罕见特征）。Navigen的药物发现平台采用对映体筛选技术（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。该平台技术已经通过鉴定出一种有前途的抗hiv临床前候选药物成功验证，这是已知的最特异性和最有效的d肽抑制剂。Navigen的抗HIV d -肽靶向HIV包膜蛋白上的一个保守区域n -三聚体，该区域在病毒进入时短暂暴露。它抑制所有主要的循环HIV-1毒株，并且通过设计，具有极高的耐药屏障。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发现了类似的易受攻击的n -三聚体。这种n -三聚体将是Navigen发现工作的目标。在这个为期两年的I期SBIR中，Navigen建议鉴定和结构表征有效抑制埃博拉病毒的d -肽。在