Carboxylesterase Factors Influencing the Therapeutic Activity of Common Antiviral Medications Used for SARS-CoV-2 Infection.

ingentiumby ingentium

In Discovery Literature.

Publication date: Jun 26, 2025

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.

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Concepts Keywords
Antiviral carboxylesterases
Coronavirus COVID-19
Covid molnupiravir
Enzymes nirmatrelvir
Extensive remdesivir

Semantics

Type Source Name
disease MESH SARS-CoV-2 Infection
pathway REACTOME SARS-CoV-2 Infection
disease IDO host
drug DRUGBANK Favipiravir
disease IDO replication
pathway KEGG Viral replication
disease IDO production
pathway REACTOME Metabolism
disease IDO role
disease IDO cell
pathway KEGG Drug metabolism
disease MESH infections
disease MESH complications
disease MESH emergency
disease MESH mutation rate
drug DRUGBANK Serine
disease IDO infection
disease IDO infectivity
drug DRUGBANK Oxygen
pathway KEGG Endocytosis
drug DRUGBANK Adenosine
drug DRUGBANK Cytidine
drug DRUGBANK Uridine
drug DRUGBANK Guanine
disease IDO site
pathway REACTOME Release
drug DRUGBANK Guanosine
drug DRUGBANK Ritonavir
drug DRUGBANK Trestolone
pathway REACTOME Immune System
disease MESH liver failure
drug DRUGBANK Ethanol
disease IDO blood
disease MESH viral infections
disease MESH inflammation
disease MESH cytokine storms
drug DRUGBANK Glycine
drug DRUGBANK Glutamic Acid
disease MESH heterozygotes
drug DRUGBANK Enalapril
drug DRUGBANK Capecitabine
disease MESH hand foot syndrome
drug DRUGBANK Oseltamivir
drug DRUGBANK Dabigatran
drug DRUGBANK Methylphenidate
disease MESH drug interactions
drug DRUGBANK Gemcitabine
drug DRUGBANK Irinotecan
drug DRUGBANK Clopidogrel
drug DRUGBANK Orlistat
disease MESH clinical relevance
disease MESH tumor
drug DRUGBANK Acetylsalicylic acid
drug DRUGBANK Acetate ion
drug DRUGBANK Tenofovir alafenamide
drug DRUGBANK Tenofovir
drug DRUGBANK L-Alanine
disease MESH bleeding
pathway KEGG Metabolic pathways
disease IDO toxin
drug DRUGBANK Ilex paraguariensis leaf
disease IDO primary infection
drug DRUGBANK Isoxaflutole
pathway KEGG ABC transporters
drug DRUGBANK Spinosad
drug DRUGBANK Coenzyme M
disease IDO susceptibility
disease IDO process
disease IDO protein
disease MESH critically ill
disease MESH immunocompromised patient
disease IDO history
disease MESH Influenza
drug DRUGBANK (S)-Des-Me-Ampa
drug DRUGBANK Chloroquine
drug DRUGBANK Borneol
drug DRUGBANK Trandolapril
disease MESH Hypertension
disease MESH ADHD
disease MESH atrial fibrillation
disease MESH Adverse Drug Reactions
drug DRUGBANK Fesoterodine
disease MESH Thrombus
drug DRUGBANK Dabigatran etexilate
pathway REACTOME Apoptosis
drug DRUGBANK Carboxyamidotriazole
drug DRUGBANK Mycophenolic acid
disease IDO algorithm
drug DRUGBANK Sodium hydroxide
disease IDO symptom

Original Article

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