Small Molecule Inhibitors of the Poxvirus Type I Interferon Binding Protein

描述（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），其也是巴西和印度人畜共患疾病的原因，以及小鼠病原体鼠痘病毒（ECTV），其在小鼠中引起小鼠痘，并且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（本文中T1-IFN bp），其从感染的细胞分泌以在细胞外环境中和在细胞表面充当T1-IFN的诱饵受体。以这种方式，T1-IFNbp抑制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毒力是必不可少的，并且是疫苗接种的有效靶标。 新的初步结果显示，当在感染后（dpi）5天给予时，抑制T1-IFNbp与T1-IFN结合的抗T1-IFNbp单克隆抗体（mAb）（而非抑制性mAb）可以治愈致死性鼠痘。 这表明了新的和令人兴奋的可能性，即1-IFNbp-T1-IFN结合的破坏可能是人类OPV感染的有效治疗。然而，用小鼠单克隆抗体治疗并不理想，因为它们昂贵并且可能在人体中引起不期望的免疫应答。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（目标1），并测试它们治愈小鼠痘的能力，小鼠痘是OPV疾病的杰出小动物模型（目标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。开发一种新的抗口服脊髓灰质炎病毒的简单药物制剂，应能对地方性和人畜共患MPXV、CPXV、VACV和水牛痘病毒地区的人类健康产生影响，在出现口服脊髓灰质炎病毒或生物恐怖袭击的情况下可能极为重要。

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.