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：
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
项目类别：
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

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. 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）是一种丝状病毒，会导致人类和非人类灵长类动物的高度致命的出血热。自1976年在中非发现中部以来，已经发生了16次自然爆发，平均死亡率为67％。没有批准的药物可以预防或治疗埃博拉病毒感染。由于埃博拉病毒的易于传播，高致死性和引起广泛恐慌的能力，CDC将其定义为生物疗法的类别，即它们最高关注的类别。非常需要有效的EBOV预防和/或治疗，既要抗击自然暴发，又要进行库存以进行潜在的生物侵袭。该项目描述了一种创新的策略，可以识别新颖的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，因此具有长期体内半衰期和降低免疫原性的显着治疗潜力。作为肽，它们可以很容易地破坏具有高效力和特异性（小分子抑制剂的罕见性状）的“不良”大蛋白/蛋白质界面。 Navigen的药物发现平台采用了对映体筛选技术（镜像噬菌体显示），并加上蛋白质设计，以识别在尝试进入细胞时停止病毒的D肽。通过确定有前途的抗HIV临床前候选者，该平台技术已成功验证，该候选者是最特定，最有效的D肽抑制剂。 Navigen的抗HIV D肽靶向在HIV包膜蛋白N-Trimer上发现的保守区域，该区域在病毒进入过程中瞬时暴露。它抑制所有主要循环的HIV-1菌株，并通过设计具有极高的阻力障碍。埃博拉病毒采用了高度相似的病毒进入机制，并且在埃博拉病毒表面上已经鉴定出类似的脆弱的n-Trimer。该N-Trimer将成为Navigen发现工作的目标。在这两年的I期SBIR中，Navigen提议鉴定并在结构上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肽将推进体内功效和毒性研究。公共卫生相关性：埃博拉病毒是高度致命的出血热的原因，没有批准的治疗剂或预防剂。自1970年代以来，它一直是非洲自然暴发的原因，并且作为潜在的生物疗法（A类，CDC）是一个严重的风险。纳维根（Navigen）正在开发一种强大而新颖的埃博拉病毒感染抑制剂，该抑制剂将满足自然患者人群的未满足需求，并要求库存打击生物侵蚀攻击。