Uncovering cellular substrates of 3C-like proteases to identify conserved virus-host interactions as antiviral targets

当今扰乱社会的许多病毒都有远亲关系：其中包括导致COVID-19大流行的病原体SARS-CoV-2，以及导致肠胃炎流行的诺如病毒。这些病毒是冠状病毒和杯状病毒家族的成员，它们与小核糖核酸病毒家族有共同的元素，包括一种酶：一种3C或类似3C的蛋白酶，它可以切割病毒和细胞蛋白质。在大多数情况下，我们不知道在病毒感染期间这些3c样蛋白酶靶向哪些人类细胞蛋白。在这个提议中，我将从一系列包含重要人类病原体的RNA病毒中鉴定所有被3c样蛋白酶切割的细胞蛋白。我将测试这些蛋白质，看看它们是否对病毒感染至关重要，然后发现3c样蛋白酶的切割如何调节病毒感染细胞中目标蛋白质的功能。目前大多数抗病毒策略用抑制剂（直接作用抗病毒药物）靶向病毒蛋白。然而，针对一种尚未出现的未知疾病X，产生针对病毒靶点的直接抗病毒药物是一项艰巨的挑战，因为它需要设计针对可能相似的靶点的药物，但就其定义而言，这些靶点事先是未知的。另一种方法是使用靶向宿主的抗病毒药物，这种药物寻求抑制存在于我们细胞中的病毒复制所需的蛋白质。我们最近的工作发现，被病毒蛋白酶靶向的蛋白质代表了宿主靶向抗病毒药物的有希望的靶标。通过确定和表征病毒家族内部和之间保守的病毒蛋白酶的共同靶点，我们为产生广谱抗病毒药物开辟了新的途径，以满足当前和未来流行病的需要。

Many of the viruses disrupting society today are distantly related: these include SARS-CoV-2, the agent behind the COVID-19 pandemic, and norovirus which causes epidemics of gastroenteritis. These viruses are members of the coronavirus and calicivirus families, and along with the picornavirus family share common elements, including an enzyme: a 3C or 3C-like protease, which cleaves viral and cellular proteins.In the majority of cases, we do not know which human cell proteins are targeted by these 3C-like proteases during viral infection. For this proposal, I will identify all the cellular proteins cleaved by 3C-like proteases from a range of RNA viruses encompassing important human pathogens. I will test these proteins to see if they are essential for virus infection and then discover how cleavage by 3C-like proteases modulates the function of the target proteins in virus-infected cells. Most current antiviral strategies target viral proteins with an inhibitor (direct-acting antivirals). However, generating direct-acting antivirals against viral targets for a yet-unknown disease X that has yet to appear represents a formidable challenge, as it requires designing drugs against targets that may be similar, but by their very definition, are unknowable beforehand. An alternative approach would employ host-targeting antivirals, which seek to inhibit proteins present in our cells that a virus needs for its replication. Our recent work found that proteins targeted by viral proteases represent promising targets for host-targeting antivirals. By identifying and characterizing common targets for viral proteases conserved within and between virus families, we open new avenues to generating broad-acting antivirals to meet the needs of current and future pandemics.