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Therapeutic strategy targeting host lipolysis limits infection by SARS-CoV-2 and influenza A virus.
Baek, Yeong-Bin; Kwon, Hyung-Jun; Sharif, Muhammad; Lim, Jeongah; Lee, In-Chul; Ryu, Young Bae; Lee, Jae-In; Kim, Ji-Sun; Lee, Young-Seung; Kim, Dong-Hoon; Park, Sang-Ik; Kim, Don-Kyu; Kim, Jeong-Sun; Choy, Hyon E; Lee, Sunwoo; Choi, Hueng-Sik; Osborne, Timothy F; Jeon, Tae-Il; Cho, Kyoung-Oh.
  • Baek YB; Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Kwon HJ; Functional Biomaterial Research Center, Korea Research Institute of Bioscience & Biotechnology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea.
  • Sharif M; Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Lim J; Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Lee IC; Functional Biomaterial Research Center, Korea Research Institute of Bioscience & Biotechnology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea.
  • Ryu YB; Functional Biomaterial Research Center, Korea Research Institute of Bioscience & Biotechnology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea.
  • Lee JI; Functional Biomaterial Research Center, Korea Research Institute of Bioscience & Biotechnology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea.
  • Kim JS; Korean Collection for Type Cultures, Korea Research Institute of Bioscience & Biotechnology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea.
  • Lee YS; Department of Animal Science, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Kim DH; Department of Pharmacology, Korea University College of Medicine, Seoul, 02841, Republic of Korea.
  • Park SI; Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Kim DK; Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Kim JS; Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Choy HE; Department of Microbiology, Chonnam National University Medical School, Gwangju, 61486, Republic of Korea.
  • Lee S; Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Choi HS; School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • Osborne TF; Institute for Fundamental Biomedical Research, Department of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, St. Petersburg, FL, 33701, USA.
  • Jeon TI; Department of Animal Science, Chonnam National University, Gwangju, 61186, Republic of Korea. tjeon@jnu.ac.kr.
  • Cho KO; Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea. choko@jun.ac.kr.
Signal Transduct Target Ther ; 7(1): 367, 2022 10 17.
Article in English | MEDLINE | ID: covidwho-2077027
ABSTRACT
The biosynthesis of host lipids and/or lipid droplets (LDs) has been studied extensively as a putative therapeutic target in diverse viral infections. However, directly targeting the LD lipolytic catabolism in virus-infected cells has not been widely investigated. Here, we show the linkage of the LD-associated lipase activation to the breakdown of LDs for the generation of free fatty acids (FFAs) at the late stage of diverse RNA viral infections, which represents a broad-spectrum antiviral target. Dysfunction of membrane transporter systems due to virus-induced cell injury results in intracellular malnutrition at the late stage of infection, thereby making the virus more dependent on the FFAs generated from LD storage for viral morphogenesis and as a source of energy. The replication of SARS-CoV-2 and influenza A virus (IAV), which is suppressed by the treatment with LD-associated lipases inhibitors, is rescued by supplementation with FFAs. The administration of lipase inhibitors, either individually or in a combination with virus-targeting drugs, protects mice from lethal IAV infection and mitigates severe lung lesions in SARS-CoV-2-infected hamsters. Moreover, the lipase inhibitors significantly reduce proinflammatory cytokine levels in the lungs of SARS-CoV-2- and IAV-challenged animals, a cause of a cytokine storm important for the critical infection or mortality of COVID-19 and IAV patients. In conclusion, the results reveal that lipase-mediated intracellular LD lipolysis is commonly exploited to facilitate RNA virus replication and furthermore suggest that pharmacological inhibitors of LD-associated lipases could be used to curb current COVID-19- and future pandemic outbreaks of potentially troublesome RNA virus infection in humans.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Orthomyxoviridae Infections / COVID-19 Drug Treatment / Lipolysis Limits: Animals / Humans Language: English Journal: Signal Transduct Target Ther Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Orthomyxoviridae Infections / COVID-19 Drug Treatment / Lipolysis Limits: Animals / Humans Language: English Journal: Signal Transduct Target Ther Year: 2022 Document Type: Article