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

今天扰乱社会的许多病毒都是遥远的亲缘关系：包括新冠肺炎大流行背后的病原体SARS-CoV-2，以及导致胃肠炎流行的诺沃克病毒。这些病毒是冠状病毒和杯状病毒家族的成员，与微小冠状病毒家族有共同的成分，包括一种酶：一种分解病毒和细胞蛋白的3C或3C样蛋白酶。在大多数情况下，我们不知道在病毒感染过程中，这些3C样蛋白酶针对的是哪些人类细胞蛋白。对于这项提议，我将从一系列包含重要人类病原体的RNA病毒中鉴定出被类似3C的蛋白酶切割的所有细胞蛋白。我将测试这些蛋白质，看看它们是否对病毒感染至关重要，然后发现在病毒感染的细胞中，类似3C的蛋白酶是如何切割调控目标蛋白质的功能的。大多数目前的抗病毒策略都是通过一种抑制剂(直接作用的抗病毒药物)来针对病毒蛋白。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作用抗病毒药物是一项艰巨的挑战，因为它需要针对可能相似但根据其定义预先未知的靶点设计药物。另一种方法是使用宿主靶向抗病毒药物，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，病毒蛋白酶靶向的蛋白质是宿主靶向抗病毒药物的有希望的靶点。通过确定和确定病毒家族内和病毒家族之间保守的病毒蛋白水解酶的共同靶点，我们开辟了产生广泛作用的抗病毒药物以满足当前和未来大流行需求的新途径。

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.