Greene Kai Su, Choi Annette, Chen Matthew, Yang Nianhui, Li Ruizhi, Qiu Yijian, Lukey Michael J, Rojas Katherine S, Shen Jonathan, Wilson Kristin F, Katt William P, Whittaker Gary R, Cerione Richard A
bioRxiv. 2023 Sep 28:2023.09.27.559756. doi: 10.1101/2023.09.27.559756.
Developing therapeutic strategies against COVID-19 has gained widespread interest given the likelihood that new viral variants will continue to emerge. Here we describe one potential therapeutic strategy which involves targeting members of the glutaminase family of mitochondrial metabolic enzymes (GLS and GLS2), which catalyze the first step in glutamine metabolism, the hydrolysis of glutamine to glutamate. We show three examples where GLS expression increases during coronavirus infection of host cells, and another in which GLS2 is upregulated. The viruses hijack the metabolic machinery responsible for glutamine metabolism to generate the building blocks for biosynthetic processes and satisfy the bioenergetic requirements demanded by the 'glutamine addiction' of virus-infected host cells. We demonstrate how genetic silencing of glutaminase enzymes reduces coronavirus infection and that newer members of two classes of small molecule allosteric inhibitors targeting these enzymes, designated as SU1, a pan-GLS/GLS2 inhibitor, and UP4, which is specific for GLS, block viral replication in mammalian epithelial cells. Overall, these findings highlight the importance of glutamine metabolism for coronavirus replication in human cells and show that glutaminase inhibitors can block coronavirus infection and thereby may represent a novel class of anti-viral drug candidates.
Inhibitors targeting glutaminase enzymes block coronavirus replication and may represent a new class of anti-viral drugs.
鉴于新的病毒变种可能会持续出现，开发针对新冠病毒的治疗策略已引起广泛关注。在此，我们描述一种潜在的治疗策略，该策略涉及靶向线粒体代谢酶谷氨酰胺酶家族（GLS和GLS2）的成员，这些酶催化谷氨酰胺代谢的第一步，即将谷氨酰胺水解为谷氨酸。我们展示了三个在宿主细胞感染冠状病毒期间GLS表达增加的例子，以及另一个GLS2上调的例子。病毒劫持负责谷氨酰胺代谢的代谢机制，以生成生物合成过程所需的构件，并满足病毒感染的宿主细胞“谷氨酰胺成瘾”所要求的生物能量需求。我们证明了谷氨酰胺酶的基因沉默如何减少冠状病毒感染，以及两类靶向这些酶的小分子变构抑制剂的新成员，即泛GLS/GLS2抑制剂SU1和对GLS特异的UP4，如何阻断哺乳动物上皮细胞中的病毒复制。总体而言，这些发现突出了谷氨酰胺代谢对冠状病毒在人类细胞中复制的重要性，并表明谷氨酰胺酶抑制剂可以阻断冠状病毒感染，从而可能代表一类新型抗病毒药物候选物。
靶向谷氨酰胺酶的抑制剂可阻断冠状病毒复制，可能代表一类新型抗病毒药物。
