Small Molecule Inhibitors of the Poxvirus Type I Interferon Binding Protein

描述（由申请人提供）：正痘病毒属（OPV）包括人类病原体天花病毒（VARV），人畜共患病毒猴痘（MPXV）和牛痘病毒（CPXV），疫苗种牛痘病毒（VAC）也负责巴西和印度的人畜共患疾病，以及小鼠病原体鼠痘病毒（ECTV），引起小鼠的鼠痘，是人类天花的杰出模型。所有opv编码高度保守（~87%相同残基）的1型干扰素（T1-IFN）结合蛋白（T1-IFN bp），该蛋白由感染细胞分泌，在细胞外环境和细胞表面充当T1-IFN的诱骗受体。通过这种方式，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OPV毒力至关重要，并且是疫苗接种的有效靶点。新的初步结果表明，一种抑制t1 - ifnbp与T1-IFN结合的抗t1 - ifnbp单克隆抗体（mAb）（而非非抑制性mAb）在感染后5天（dpi）给予可治愈致死性鼠痘。这提示了一种新的令人兴奋的可能性，即破坏1-IFNbp-T1-IFN结合可能是人类OPV感染的有效治疗方法。然而，用小鼠单克隆抗体治疗并不理想，因为它们价格昂贵，并且可能在人体中引起不良的免疫反应。T1-IFN bp的小分子药理学抑制剂将是更好的方法。因此，我们将筛选抑制T1-IFN bp-T1-IFN的小分子（Aim 1），并测试它们治疗鼠痘的能力，鼠痘是一种出色的OPV疾病小动物模型（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疾病的替代品进行测试。开发一种针对口服脊髓灰质炎病毒的新型简单药物学制剂，应对流行和人畜共患的MPXV、CPXV、VACV和水痘病毒领域的人类健康产生影响，并可能在出现口服脊髓灰质炎病毒或生物恐怖袭击的情况下发挥极端重要的作用。

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.