Home Medizin Paxlovid erweitert die Behandlungsmöglichkeiten für COVID-19-Patienten

Paxlovid erweitert die Behandlungsmöglichkeiten für COVID-19-Patienten

von NFI Redaktion

Recently, a review was published in Pharmacy, in which a group of authors examined the design, synthesis, and mechanism of action of Paxlovid, a drug combination of protease inhibitors (PIs) for the treatment of Coronavirus Disease 2019 (COVID-19).





Study: The design, synthesis, and mechanism of action of Paxlovid, a protease inhibitor drug combination for the treatment of COVID-19. Image credit: Tobias Arhelger/Shutterstock.com

Background

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has presented significant challenges to global health systems and medical science.

In response, researchers worldwide developed vaccines with innovative mechanisms and small-molecule antivirals targeting key viral proteins.

Among these, PaxlovidTM, a combination of Nirmatrelvir and Ritonavir PIs, stands out for its efficacy in treating COVID-19.

Nirmatrelvir inhibits the main protease of SARS-CoV-2, which is vital for virus replication, while Ritonavir enhances the effectiveness of Nirmatrelvir by inhibiting Cytochrome P450 3A4 (CYP3A4), an enzyme that would otherwise quickly break down Nirmatrelvir.

Despite the success of the Nirmatrelvir-Ritonavir combination, further research is needed to develop alternative main protease inhibitors (MPro) that ensure sustained efficacy against COVID-19.

PIs as Antivirals Against Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV)

PI Medications Against HCV and HIV Infections

PIs are vital in the treatment of HCV and HIV infections. HCV, a small RNA virus causing liver diseases, is targeted by PIs such as Asunaporevir, Telaprevir, and Boceprevir, with a focus on the nonstructural (NS)3/4A serine protease.

These inhibitors are peptide mimetics containing peptide bonds and a „warhead“ group that covalently but reversibly binds to the active site of the enzyme.

HIV PIs target the aspartic protease of the virus, essential for virus replication, and are used in antiretroviral therapy, transforming HIV from deadly to chronic.

Development and Mechanism of Action of Nirmatrelvir

Nirmatrelvir, developed from Pfizer’s previous SARS-CoV-1 PI, PF-00835231, faced challenges in oral absorption.

Modifications, such as changing the warhead and exchanging different molecular components, increased its binding affinity and antiviral activity, ultimately leading to Nirmatrelvir with a nitrile warhead, improving solubility and synthesis.

Despite different warheads, its structural similarity to Boceprevir and its role as a covalent inhibitor of SARS-CoV-2 Mpro are significant for the treatment of COVID-19.

Synthesis of Nirmatrelvir

The synthesis of Nirmatrelvir involves coupling the P1 moiety and the P2-P3 dipeptide, with the last step being the formation of the nitrile warhead.

The process starts with protected amino acid derivatives and progresses through stages such as Boc deprotection, ester cleavage, and dipeptide formation.

The synthesis delivers Nirmatrelvir with high efficiency and introduces a new approach involving a Ugi-type three-component reaction for higher diastereoselectivity.

Synthesis and Structure-Activity Relationship Study (SAR) of Nirmatrelvir Analogs

Research by Chia and colleagues led to the synthesis of Nirmatrelvir analogs with different P1′ moieties, investigating the role of the warhead in antiviral activity.

These studies demonstrated varying degrees of efficacy in protease inhibition and antiviral activity, with some derivatives showing similar or better effects than Nirmatrelvir. However, challenges in cell penetration and specificity toward SARS-CoV-2 limited the broader application of these analogs.

Novel Covalent and Noncovalent Inhibitors of SARS-CoV-2 Mpro

Recent developments in SARS-CoV-2 Mpro inhibitors have introduced both peptide mimetic and non-peptidic inhibitors.

These include warheads such as epoxide rings and fluoromethyl groups, offering alternative mechanisms of covalent binding to the enzyme.

Noncovalent inhibitors such as Ensitrelvir show lower reactivity due to their secondary interaction nature, but better selectivity. These developments represent crucial steps in diversifying therapy options against COVID-19 and its evolving strains.

Ritonavir as a Pharmacokinetic Enhancer

Structure, Activity, and Interactions of Ritonavir

Ritonavir was originally an HIV protease inhibitor and is known for its efficacy at low doses (~100 mg) in inhibiting the CYP3A4 enzyme, a crucial element in drug metabolism.

While high doses of Ritonavir are poorly tolerated, its effectiveness at low doses in combination therapies with other HIV protease inhibitors extends their half-life, reducing the required dosages.

This unique use of Ritonavir has been investigated in early COVID-19 treatments. However, its use poses the risk of significant drug interactions, especially with drugs metabolized by CYP3A4, potentially reaching toxic concentrations.

Additionally, the effect of Ritonavir on other enzymes and transport proteins, although of lesser importance in Paxlovid treatment, is noted.

Synthesis of Ritonavir

The synthesis of Ritonavir developed in Abbott Laboratories encompasses complex chemical processes, combining chiral amine and carboxylic acid moieties.

The synthesis starts with a cyclocondensation reaction between thioformamide and ethyl-2-chloroacetate, followed by a series of steps leading to the formation of Ritonavir.

This complicated process involves various intermediates and chemical reactions, including triethylamine and 4-dimethylaminopyridine, emphasizing the complexity required in pharmaceutical synthesis.

The production of Ritonavir demonstrates the complex chemical techniques needed to develop effective pharmaceutical agents.

Paxlovid – Application and Activity Against Mutated Variants

Paxlovid, a combination of Nirmatrelvir and Ritonavir, has shown significant efficacy in reducing hospitalizations and mortality associated with COVID-19.

While it has received emergency use authorization in various regions, its efficacy against emerging strains and mutant variants is continually under review.

The evolving landscape of SARS-CoV-2 mutations requires continuous monitoring to ensure the sustainable efficacy of treatments like Paxlovid.

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