Shen Yue, Eades William, Dinh Linh, Yan Bingfang
Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45229, USA.
Pharmaceutics. 2025 Jun 26;17(7):832. doi: 10.3390/pharmaceutics17070832.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, remains a major global health threat. The virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Several small-molecule antiviral drugs, including molnupiravir, favipiravir, remdesivir, and nirmatrelvir have been shown to inhibit SARS-CoV-2 replication and are approved for treating SARS-CoV-2 infections. Nirmatrelvir inhibits the viral main protease (M), a key enzyme for processing polyproteins in viral replication. In contrast, molnupiravir, favipiravir, and remdesivir are prodrugs that target RNA-dependent RNA polymerase (RdRp), which is crucial for genome replication and subgenomic RNA production. However, undergoing extensive metabolism profoundly impacts their therapeutic effects. Carboxylesterases (CES) are a family of enzymes that play an essential role in the metabolism of many drugs, especially prodrugs that require activation through hydrolysis. Molnupiravir is activated by carboxylesterase-2 (CES2), while remdesivir is hydrolytically activated by CES1 but inhibits CES2. Nirmatrelvir and remdesivir are oxidized by the same cytochrome P450 (CYP) enzyme. Additionally, various transporters are involved in the uptake or efflux of these drugs and/or their metabolites. It is well established that drug-metabolizing enzymes and transporters are differentially expressed depending on the cell type, and these genes exhibit significant polymorphisms. In this review, we examine how CES-related cellular and genetic factors influence the therapeutic activities of these widely used COVID-19 medications. This article highlights implications for improving product design, targeted inhibition, and personalized medicine by exploring genetic variations and their impact on drug metabolism and efficacy.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是导致COVID-19的病毒，仍然是全球主要的健康威胁。该病毒通过与血管紧张素转换酶2（ACE2）受体结合进入宿主细胞。几种小分子抗病毒药物，包括莫努匹拉韦、法匹拉韦、瑞德西韦和奈玛特韦，已被证明可抑制SARS-CoV-2复制，并被批准用于治疗SARS-CoV-2感染。奈玛特韦抑制病毒主要蛋白酶（M），这是病毒复制过程中处理多聚蛋白的关键酶。相比之下，莫努匹拉韦、法匹拉韦和瑞德西韦是前体药物，它们靶向RNA依赖性RNA聚合酶（RdRp），这对基因组复制和亚基因组RNA的产生至关重要。然而，经历广泛的代谢会深刻影响它们的治疗效果。羧酸酯酶（CES）是一类酶，在许多药物的代谢中起着重要作用，尤其是那些需要通过水解激活的前体药物。莫努匹拉韦由羧酸酯酶-2（CES2）激活，而瑞德西韦由CES1水解激活，但会抑制CES2。奈玛特韦和瑞德西韦被同一种细胞色素P450（CYP）酶氧化。此外，各种转运蛋白参与这些药物和/或其代谢物的摄取或外排。众所周知，药物代谢酶和转运蛋白的表达因细胞类型而异，并且这些基因表现出显著的多态性。在这篇综述中，我们研究了与CES相关的细胞和遗传因素如何影响这些广泛使用的COVID-19药物的治疗活性。本文强调了通过探索基因变异及其对药物代谢和疗效的影响，对改进产品设计、靶向抑制和个性化医疗的意义。
