A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (M^pro) of SARS-CoV-2 and MERS-CoV

JACS Au, Год журнала: 2024, Номер 4(8), С. 3217 - 3227

Опубликована: Июль 30, 2024

Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from USA Food Drug Administration (FDA) entered phase III clinical trials as a possible replacement Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M

Язык: Английский

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A patent review of CYP3A4 inhibitors (2018 - present)

Expert Opinion on Therapeutic Patents, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Introduction Cytochrome P450 3A4 (CYP3A4), one of the most important xenobiotic-metabolizing enzymes, plays a central role in drug metabolism and acts as key mediator drug-drug interactions. CYP3A4 inhibitors can potentiate vivo therapeutic effects CYP3A4-substrate drugs via enhancing their systematic exposure levels. Two (ritonavir cobicistat) have already been approved for modulating levels drugs.

Язык: Английский

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Latest advances in research methods for high-yield cellulase production

Sustainable Energy & Fuels, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Lignocellulosic biomass, due to its accessibility, abundance, and environmental friendliness, has become a promising renewable resource.

Язык: Английский

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Insight into the Role of the Aryl Hydrocarbon Receptor in Bovine Coronavirus Infection by an Integrated Approach Combining In Vitro and In Silico Methods

Microorganisms, Год журнала: 2025, Номер 13(3), С. 579 - 579

Опубликована: Март 4, 2025

It is well known that the host response to different human and animal coronaviruses infection regulated by aryl hydrocarbon receptor, a ligand-activated transcription factor. The present study investigates expression of receptor during bovine coronavirus infection, through in vitro silico investigations. studies demonstrate as its targets, CYP1A1 CYP1B1, were significantly activated cells (MDBK). During pretreatment with non-cytotoxic doses CH223191, selective inhibitor resulted significant reduction virus yield downregulation viral spike protein expression. These findings occurred presence inhibition signaling. Our results reveal acts on replication, upregulating downstream target proteins, CYP1B1. In addition, following studies, three-dimensional structural model complex antagonist CH223191 indicates molecular mechanism, which PASB TAD domains interact inhibitor, mainly driven an extensive network hydrophobic interactions, series hydrogen bonds contributing stabilizing complex. Interestingly, bioinformatic analyses revealed high similarity at primary sequence structure levels. Taken together, these represent fundamental step for development innovative drugs targeting AhR potential object CoVs therapy.

Язык: Английский

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Advancing Viral Defense: Unravelling the Potential of Host-Directed Antivirals Against SARS-CoV-2

Drugs and Drug Candidates, Год журнала: 2025, Номер 4(2), С. 13 - 13

Опубликована: Март 28, 2025

The COVID-19 pandemic, driven by the high transmissibility and immune evasion caused SARS-CoV-2 its variants (e.g., Alpha, Delta, Omicron), has led to massive casualties worldwide. As of November 2024, International Committee on Taxonomy Viruses (ICTV) identified 14,690 viral species across 3522 genera. increasing infectious resistance FDA EMA-approved antivirals, such as 300-fold efficacy reduction in Nirmatrelvir against 3CLpro, highlight need for mutation-stable likewise targeting essential host proteins like kinases, heat shock proteins, lipid metabolism immunological pathway etc. Unlike direct-acting HDAs reduce risk conserved replication. proposal repurposing current FDA-approved drugs host-directed antiviral (HDA) approach is not new, Ouabain, a sodium-potassium ATPase inhibitor herpes simplex virus (HSV) Verapamil, calcium channel blocker influenza A (IAV), name few. Given colossal potential HDA exterminate infection, it been increasingly studied SARS-CoV-2. This review aims unravel interaction between viruses human hosts their successfully proposed provide insight into an alternative treatment rampant mutation benefits, limitations, protein-targeted therapies prospects are also covered this review.

Язык: Английский

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Genetic Predictors of Paxlovid Treatment Response: The Role of IFNAR2, OAS1, OAS3, and ACE2 in COVID-19 Clinical Course

Journal of Personalized Medicine, Год журнала: 2025, Номер 15(4), С. 156 - 156

Опубликована: Апрель 17, 2025

Background: This study investigated the role of genetic polymorphisms in IFNAR2, OAS1, OAS3, and ACE2 as predictors Paxlovid treatment response, specifically examining their influence on clinical course laboratory parameters COVID-19 patients. Methods: We analyzed impact genes associated with interferon pathway (IFNAR2 rs2236757), antiviral response (OAS1 rs10774671, OAS3 rs10735079), viral entry (ACE2 rs2074192) individuals treated Paxlovid. Results: Our findings suggest that variations these may modulate immune coagulation pathways context during infection. Specifically, IFNAR2 rs2236757 G allele was alterations inflammatory markers, while OAS1 influenced parameters. Furthermore, specific genotypes were linked to changes such oxygen saturation, leukocyte count, liver function markers Paxlovid-treated Conclusions: These results highlight potential considering factors understanding individual responses informing future personalized approaches.

Язык: Английский

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Recent highlights in covalent inhibitor design

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Synthesis of 3′-modified xylofuranosyl nucleosides bearing 5′-silyl or -butyryl groups and their antiviral effect against RNA viruses

European Journal of Pharmaceutical Sciences, Год журнала: 2025, Номер unknown, С. 107107 - 107107

Опубликована: Апрель 1, 2025

Язык: Английский

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Nirmatrelvir: From Discovery to Modern and Alternative Synthetic Approaches

Processes, Год журнала: 2024, Номер 12(6), С. 1242 - 1242

Опубликована: Июнь 17, 2024

The global urgency in response to the COVID-19 pandemic has catalyzed extensive research into discovering efficacious antiviral compounds against SARS-CoV-2. Among these, Nirmatrelvir (PF-07321332) emerged as a promising candidate, exhibiting potent activity by targeting main protease of SARS-CoV-2, and been marketed combination with ritonavir first oral treatment for name PaxlovidTM. This review outlines synthetic approaches Nirmatrelvir, ranging from Pfizer’s original method newer, more sustainable strategies, such flow chemistry strategies multicomponent reactions. Each approach’s novelty contributions yield purification processes are highlighted. Additionally, synthesis key fragments comprising innovative optimization discussed.

Язык: Английский

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Simultaneous screening for selective SARS-CoV-2, Lassa, and Machupo virus entry inhibitors

SLAS DISCOVERY, Год журнала: 2024, Номер 29(6), С. 100178 - 100178

Опубликована: Авг. 17, 2024

Emerging highly pathogenic viruses can pose profound impacts on global health, the economy, and society. To meet that challenge, National Institute of Allergy Infectious Diseases (NIAID) established nine Antiviral Drug Discovery (AViDD) centers for early-stage identification validation novel antiviral drug candidates against with pandemic potential. As part this initiative, we paired entry assays simultaneously screen inhibitors specifically targeting SARS-CoV-2 (SARS2), Lassa virus (LASV) Machupo (MACV) entry. do so employed a dual pseudotyped (PV) infection system allowing us to ∼650,000 compounds efficiently cost-effectively. Adaptation these into 1536 well-plate format ultra-high throughput screening (uHTS) resulted in largest ever conducted our facility, over 2.4 million wells completed. The allowed detect two PV infections simultaneously: LASV + MACV, MACV SARS2, SARS2 LASV. Each contains different luciferase reporter gene which enabled measure each exclusively, albeit same well. was screened at least twice utilizing reporters, select specific particular exclude those hit off targets, including cellular components or proteins. All were robust an average Z' value ranging from 0.5 0.8. primary 1812, 1506, 2586 unique hits LASV, respectively. confirmation narrowed list further 60, 40, 90 are Of compounds, 8, 35, 50 showed IC50 < 10 μM, some have much greater potency excellent activity profiles none cytotoxic. These selected currently being studied their mechanism action improve specificity through chemical modification.

Язык: Английский

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