Small Molecule Inhibitors of the Poxvirus Type I Interferon Binding Protein

I 型痘病毒干扰素结合蛋白的小分子抑制剂

• 批准号: 8401099
• 负责人: JEFFREY R PETERSON
• 金额: $ 24.35万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401099
• 关键词: Africa; Animal Model; Antiviral Agents; Area; Binding; Binding Proteins; Binding Sites; Biological; Bioterrorism; Brazil; Cell surface; Cells; Characteristics; Chemicals; Cowpox; Cowpox virus; Development; Disease; Drug Kinetics; Emergency Situation; Endemic Diseases; Goals; Health; Human; Immune response; In Vitro; India; Infection; Infectious Ectromelia; Interferon Type I; Interferons; Lead; Left; Modeling; Monkeypox; Monkeypox virus; Monoclonal Antibodies; Mouse Pox Virus; Mus; Oral Administration; Orthopoxvirus; Oryctolagus cuniculus; Pathogenesis; Pharmaceutical Preparations; Positioning Attribute; Poxviridae; Production; Research; Risk; Smallpox; Smallpox Viruses; Solubility; Staging; Testing; Toxic effect; Vaccination; Vaccines; Vaccinia virus; Viral; Viral Physiology; Virulence; Virus; Work; Zoonoses; base; drug candidate; effective therapy; extracellular; high throughput screening; improved; in vivo; inhibitor/antagonist; nonhuman primate; novel; pathogen; prevent; protein protein interaction; receptor; small molecule; tissue culture

DESCRIPTION (provided by applicant): The genus Orthopoxvirus (OPV) includes, among others, the human pathogen variola virus (VARV), the zoonotic viruses monkeypox (MPXV) and cowpox virus (CPXV)~ the vaccine species vaccinia virus (VAC) which is also responsible for zoonoses in Brazil and India, and the mouse pathogen Ectromelia virus (ECTV) that causes mousepox in mice and is an outstanding model for human smallpox. All OPVs encode a highly conserved (~87% identical residues) Type 1 interferon (T1-IFN) binding protein (herein T1-IFN bp) that is secreted from infected cells to act as a decoy receptor for T1-IFN in the extracellular milieu and at the cell surface. In this way, the T1-IFNbp suppresses the anti-viral activity of T1-IFN. Using ECTV as a model, we previously showed that T1-IFN bp is essential for OPV virulence and an effective target for vaccination. New preliminary results show that an anti-T1-IFNbp monoclonal antibody (mAb) that inhibits the binding of T1-IFN bp to T1-IFN (but not a non-inhibitory mAb) can cure lethal mousepox when given as late as 5 days post infection (dpi). This suggests the new and exciting possibility that disruption of 1-IFNbp-T1-IFN binding could be an effective treatment for human OPV infections. However, treatment with mouse mAbs is not ideal because they are expensive and can cause an undesirable immune response in humans. Small molecule pharmacological inhibitors of T1-IFN bp would be a much better approach. Hence, we will screen for small molecules that inhibit T1-IFN bp-T1-IFN (Aim 1) and test them for their ability to cure mousepox, an outstanding small animal model for OPV disease (Aim 2). If successful, these drug candidates could be tested in additional OPV animal models as surrogates of human OPV disease. Developing a new simple pharmacological agent against OPVs should have an impact for human health in areas of endemic and zoonotic MPXV, CPXV, VACV and buffalopox virus and may be of extreme importance in case of emerging OPVs or bioterrorist attacks. PUBLIC HEALTH RELEVANCE: The proposed studies are highly significant because they will identify drug candidates for the treatment of poxvirus diseases at late stages of infection. The proposed work is of significance to human health because poxviruses cause endemic diseases in India, Africa and Brazil, are possible emerging pathogens, and there is a risk they could be used as agents of bioterrorism.

描述（由申请人提供）：正质病毒属（OPV）包括人类病原体Variola病毒（VARV），人畜共患病毒Monkeypox（MPXV）和Cowpox病毒（CPXV）〜疫苗疫苗病毒（VAC）对Brazil and India and India contect and Insure（VAC）（VAC），以及该物种的疫苗（VAC）（VAC）在小鼠中引起菌丝，是人类天花的出色模型。所有OPV编码一个高度保守的（〜87％相同的残基）1型干扰素（T1-IFN）结合蛋白（本文T1-IFN BP），该蛋白从感染细胞分泌，以充当细胞外MIRIEU和细胞表面中T1-IFN的诱饵受体。这样，T1-IFNBP抑制了T1-IFN的抗病毒活性。使用ECTV作为模型，我们先前表明T1-IFN BP对于OPV毒力和有效的疫苗接种目标至关重要。 新的初步结果表明，抗T1-IFNBP单克隆抗体（MAB）抑制T1-IFN BP与T1-IFN的结合（而不是非抑制性MAB）可以在感染后5天（DPI）时治愈致命的菌群。 这表明，1-IFNBP-T1-IFN结合的破坏可能是人类OPV感染的有效治疗方法。但是，用小鼠mAb的治疗不是理想的，因为它们很昂贵，并且可能导致人类的不良免疫反应。 T1-IFN BP的小分子药理抑制剂将是一种更好的方法。因此，我们将筛选抑制T1-IFN BP-T1-IFN（AIM 1）的小分子（AIM 1），并测试它们是否可以治愈MOUSEPOX，这是OPV疾病的出色小动物模型（AIM 2）。如果成功，这些候选药物可以在其他OPV动物模型中作为人类OPV疾病的替代物进行测试。开发一种针对OPV的新的简单药理剂应对人类和人畜共患病，CPXV，VACV和Buffalopox病毒的人类健康产生影响，并且对于新兴的OPV或生物交易者攻击，可能非常重要。 公共卫生相关性：拟议的研究非常重要，因为它们将在感染后期识别候选药物来治疗痘病毒疾病。拟议的工作对人类健康具有重要意义，因为在印度，非洲和巴西引起的特有疾病是可能的新兴病原体，并且有可能将它们用作生物恐怖主义的药物。