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

基本信息

批准号：
8494568
负责人：
Brett D Welch
金额：
$ 30万
依托单位：
NAVIGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-03-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494568
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 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 screening small molecule trait transmission process

项目摘要

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.

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年在非洲中部发现以来，已发生16次人类自然疫情，平均死亡率为67%。没有批准的药物可以预防或治疗埃博拉感染。由于埃博拉病毒易于传播、致死率高且能够引起广泛恐慌，疾病预防控制中心将其定义为 A 类生物恐怖制剂，这是他们最关注的类别。非常需要有效的埃博拉病毒预防和/或治疗，既可以对抗自然爆发，也可以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，旨在识别新型 D 肽候选药物来对抗埃博拉病毒。 D 肽是天然 L 肽的镜像，不能被蛋白酶消化，因此具有长体内半衰期和降低免疫原性的显着治疗潜力。作为肽，它们可以轻松破坏“不可成药”的大蛋白质/蛋白质界面，具有高效力和特异性（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，来识别可阻止病毒试图进入细胞的 D 肽。该平台技术已通过鉴定一种有前景的抗 HIV 临床前候选药物而成功得到验证，该候选药物是已知最特异、最有效的 D 肽抑制剂。 Navigen 的抗 HIV D 肽针对 HIV 包膜蛋白 N-三聚体上的一个保守区域，该区域在病毒进入过程中短暂暴露。它可以抑制所有主要的流行 HIV-1 病毒株，并且从设计上来说，它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-三聚体将成为 Navigen 发现工作的目标。在这个为期两年的 I 期 SBIR 中，Navigen 提议鉴定和结构表征有效抑制埃博拉病毒的 D 肽。在第二阶段，抑制剂优化将完成，所得的 D 肽将进入体内功效和毒性研究。