In early 2020, severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infections leading to COVID-19 disease reached a global level leading to the World Health Organization (WHO) declaration of a pandemic. Scientists around the globe rapidly responded to try and discover novel therapeutics and repurpose extant drugs to treat the disease. This work describes the preclinical discovery efforts that led to the invention of PF-07321332 (nirmatrelvir, ), a potent and orally active inhibitor of the SARS CoV-2 main protease (M) enzyme. At the outset we focused on modifying PF-00835231 () discovered in 2004 as a potent inhibitor of the SARS CoV-1 M with poor systemic exposure. Our effort was focused on modifying with the goal of engineering in oral bioavailability by design, while maintaining cellular potency and low metabolic clearance. Modifications of ultimately led to the invention of nirmatrelvir , the M inhibitor component in PAXLOVID.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c02561 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Femtosecond laser-ablative aqueous synthesis of multi-drug antiviral nanoparticles.
Nanomedicine (Lond)
March 2025
Department of Chemistry and The Institute for Laser, Photonics, and Biophotonics, University at Buffalo, The State University of New York, Buffalo, NY, USA.
Background: Nanomedicine offers a number of innovative strategies to address major public health burdens, including complex respiratory illnesses. In this work, we introduce a multi-drug nanoparticle fabricated using femtosecond laser ablation for the treatment of influenza, SARS-CoV-2, and their co-infections.
Methods: The SARS-CoV-2 antiviral, remdesivir; the influenza antiviral, baloxavir marboxil; and the anti-inflammatory, dexamethasone, were co-crystalized and then ablated in aqueous media using a femtosecond pulsed laser and subsequently surface modified with the cationic polymer, chitosan, or poly-d-lysine.
Animal models of post-acute COVID-19 syndrome: a call for longitudinal animal studies.
Front Immunol
March 2025
Department of Public Laboratory, The Third People's Hospital of Kunming City/Infectious Disease Clinical Medical Center of Yunnan Province, Kunming, Yunnan, China.
Animal models are indispensable for unraveling the mechanisms underlying post-acute sequelae of COVID-19 (PASC). This review evaluates recent research on PASC-related perturbations in animal models, drawing comparisons with clinical findings. Despite the limited number of studies on post-COVID conditions, particularly those extending beyond three months, these studies provide valuable insights.
View Article and Find Full Text PDFAssociation between SARS-CoV-2 infection and anti-apolipoprotein A-1 antibody in children.
Front Immunol
March 2025
Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, Geneva, Switzerland.
Background And Aims: Autoantibodies against apolipoprotein A-1 (AAA1) are elicited by SARS-CoV-2 infection and predict COVID-19 symptoms persistence at one year in adults, but whether this applies to children is unknown. We studied the association of SARS-CoV-2 exposure with AAA1 prevalence in children and the association of AAA1 seropositivity with symptom persistence.
Methods: Anti-SARS-CoV-2 and AAA1 serologies were examined in 1031 participants aged 6 months to 17 years old from the prospective SEROCOV-KIDS cohort and recruited between 12.
Development of a multi-epitope vaccine candidate to combat SARS-CoV-2 and dengue virus co-infection through an immunoinformatic approach.
Front Immunol
March 2025
Division of Metabolomics, Proteomics & Imaging facility, Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Dibrugarh, Assam, India.
Background: Although the SARS-CoV-2 and dengue viruses seriously endanger human health, there is presently no vaccine that can stop a person from contracting both viruses at the same time. In this study, four antigens from SARS-CoV-2 and dengue virus were tested for immunogenicity, antigenicity, allergenicity, and toxicity and chosen to predict dominant T- and B-cell epitopes.
Methods: For designing a multi-epitope vaccine, the sequences were retrieved, and using bioinformatics and immunoinformatics, the physicochemical and immunological properties, as well as secondary structures, of the vaccine were predicted and studied.
Prevalence of bacteria, fungi, and virus coinfections with SARS-CoV-2 Omicron variant among patients with severe COVID-19 in Guangzhou, China, winter 2022.
Biosaf Health
April 2024
Institute of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510440, China.
The status of coinfection during the national outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.5.2 or BF.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!