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Human carboxylesterase 1A plays a predominant role in the hydrolytic activation of remdesivir in humans.
Zhang, Feng; Li, Hong-Xin; Zhang, Tian-Tian; Xiong, Yuan; Wang, Hao-Nan; Lu, Zhen-Hui; Xiong, Lei; He, Yu-Qi; Ge, Guang-Bo.
  • Zhang F; Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Li HX; Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Zhang TT; Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China; School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China.
  • Xiong Y; Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Wang HN; Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Lu ZH; Institute of Respiratory Disease, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Xiong L; Yunnan University of Chinese Medicine, Kunming, Yunnan, China.
  • He YQ; School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China.
  • Ge GB; Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: geguangbo@dicp.ac.cn.
Chem Biol Interact ; 351: 109744, 2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1509623
ABSTRACT
Remdesivir, an intravenous nucleotide prodrug, has been approved for treating COVID-19 in hospitalized adults and pediatric patients. Upon administration, remdesivir can be readily hydrolyzed to form its active form GS-441524, while the cleavage of the carboxylic ester into GS-704277 is the first step for remdesivir activation. This study aims to assign the key enzymes responsible for remdesivir hydrolysis in humans, as well as to investigate the kinetics of remdesivir hydrolysis in various enzyme sources. The results showed that remdesivir could be hydrolyzed to form GS-704277 in human plasma and the microsomes from human liver (HLMs), lung (HLuMs) and kidney (HKMs), while the hydrolytic rate of remdesivir in HLMs was the fastest. Chemical inhibition and reaction phenotyping assays suggested that human carboxylesterase 1 (hCES1A) played a predominant role in remdesivir hydrolysis, while cathepsin A (CTSA), acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) contributed to a lesser extent. Enzymatic kinetic analyses demonstrated that remdesivir hydrolysis in hCES1A (SHUTCM) and HLMs showed similar kinetic plots and much closed Km values to each other. Meanwhile, GS-704277 formation rates were strongly correlated with the CES1A activities in HLM samples from different individual donors. Further investigation revealed that simvastatin (a therapeutic agent for adjuvant treating COVID-19) strongly inhibited remdesivir hydrolysis in both recombinant hCES1A and HLMs. Collectively, our findings reveal that hCES1A plays a predominant role in remdesivir hydrolysis in humans, which are very helpful for predicting inter-individual variability in response to remdesivir and for guiding the rational use of this anti-COVID-19 agent in clinical settings.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Adenosine Monophosphate / Carboxylesterase / Alanine Type of study: Prognostic study Limits: Humans Language: English Journal: Chem Biol Interact Year: 2022 Document Type: Article Affiliation country: J.cbi.2021.109744

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Adenosine Monophosphate / Carboxylesterase / Alanine Type of study: Prognostic study Limits: Humans Language: English Journal: Chem Biol Interact Year: 2022 Document Type: Article Affiliation country: J.cbi.2021.109744