PF-07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID-19 patients.
PF-07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID-19 patients.
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PF-07321332（Nirmatrelvir）不与人ENT 1或ENT 2相互作用：对COVID-19患者的影响。
DOI：
10.1111/cts.13292
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
严重急性呼吸系统综合征-冠状病毒2 （SARS - CoV - 2）和随后的冠状病毒病2019 （COVID - 19）的持续大流行已导致超过610万人死亡，并引发了对病毒学的更大兴趣，以加快抗病毒药物的开发进程。美国食品和药物管理局（FDA）批准了三种抗病毒药物的紧急使用授权：remdesivir、molnupiravir和nirmatrelvir。Remdesivir和molnupiravir是核苷类似物，经过生物转化形成活性代谢物，结合到新的病毒RNA中以阻止复制。与remdesivir或molnupiravir不同，nirmatrelvir是一种蛋白酶抑制剂，可与SARS - CoV - 23c样蛋白酶共价结合，从而中断病毒复制周期。最近的一项研究发现，remdesivir和molnupiravir的活性代谢物EIDD‐1931是平衡核苷转运体1和2 （ENT1和2）的底物。尽管ENTs普遍表达，但remdesivir和molnupiravir的临床前疗效并未在大规模SARS - CoV - 2临床试验中得到反映。有趣的是，在缺氧和急性肺损伤的反应中，肺上皮细胞和内皮细胞显示了ENT1和ENT2表达的下调，尽管尚未在COVID - 19患者中直接研究。remdesivir和molnupiravir在这些患者中的不良疗效可能部分归因于肺内耳鼻喉功能的抑制，但需要进一步的研究。本研究研究了nirmatrelvir与耳鼻喉管之间的相互作用，发现它在300 μM的耳鼻喉管介导的[3H]尿苷摄取中是一种较差的抑制剂。与remdesivir或EIDD‐1931不同，ENT活性不太可能是人类对nirmatrelvir处置的一个因素；然而，这是否有助于类似的体外和临床疗效，将需要进一步的机制研究。
The ongoing pandemic of severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) and subsequently, coronavirus disease 2019 (COVID‐19), has led to the deaths of over 6.1 million people and sparked a greater interest in virology to expedite the development process for antivirals. The US Food and Drug Administration (FDA) granted emergency use authorization for three antivirals: remdesivir, molnupiravir, and nirmatrelvir. Remdesivir and molnupiravir are nucleoside analogs that undergo biotransformation to form active metabolites that incorporate into new viral RNA to stall replication. Unlike remdesivir or molnupiravir, nirmatrelvir is a protease inhibitor that covalently binds to the SARS‐CoV‐2 3C‐like protease to interrupt the viral replication cycle. A recent study identified that remdesivir and the active metabolite of molnupiravir, EIDD‐1931, are substrates of equilibrative nucleoside transporters 1 and 2 (ENT1 and 2). Despite the ubiquitous expression of the ENTs, the preclinical efficacy of remdesivir and molnupiravir is not reflected in wide‐scale SARS‐CoV‐2 clinical trials. Interestingly, downregulation of ENT1 and ENT2 expression has been shown in lung epithelial and endothelial cells in response to hypoxia and acute lung injury, although it has not been directly studied in patients with COVID‐19. It is possible that the poor efficacy of remdesivir and molnupiravir in these patients may be partially attributed to the repression of ENTs in the lungs, but further studies are warranted. This study investigated the interaction between nirmatrelvir and the ENTs and found that it was a poor inhibitor of ENT‐mediated [3H]uridine uptake at 300 μM. Unlike for remdesivir or EIDD‐1931, ENT activity is unlikely to be a factor for nirmatrelvir disposition in humans; however, whether this contributes to the similar in vitro and clinical efficacy will require further mechanistic studies.
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DOI：
10.1056/nejmoa2118542
发表时间：
2022-04-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hammond J;Leister-Tebbe H;Gardner A;Abreu P;Bao W;Wisemandle W;Baniecki M;Hendrick VM;Damle B;Simón-Campos A;Pypstra R;Rusnak JM;EPIC-HR Investigators
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EPIC-HR Investigators
COVID-19感染患者的急性肺损伤
影响因子：
10.6
作者：
Li, Liyang;Huang, Qihong;Wang, Xiangdong
通讯作者：
Wang, Xiangdong
DOI：
10.1165/rcmb.2012-0457oc
发表时间：
2013-08-01
影响因子：
6.4
作者：
Morote-Garcia, Julio C.;Koehler, David;Rosenberger, Peter
通讯作者：
Rosenberger, Peter
HIF-1依赖性抑制缺氧中平衡性核苷转运蛋白（ENT）。
DOI：
10.1084/jem.20050177
发表时间：
2005-12-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.4
作者：
Taniguchi-Ponciano K;Vadillo E;Mayani H;Gonzalez-Bonilla CR;Torres J;Majluf A;Flores-Padilla G;Wacher-Rodarte N;Galan JC;Ferat-Osorio E;Blanco-Favela F;Lopez-Macias C;Ferreira-Hermosillo A;Ramirez-Renteria C;Peña-Martínez E;Silva-Román G;Vela-Patiño S;Mata-Lozano C;Carvente-Garcia R;Basurto-Acevedo L;Saucedo R;Piña-Sanchez P;Chavez-Gonzalez A;Marrero-Rodríguez D;Mercado M
通讯作者：
Mercado M