Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19

Robinson, Philip A.; Toussi, Sima S.; Aggarwal, Sudeepta; Bergman, Arthur; Zhu, Tong; Hackman, Frances; Sathish, Jean G.; Updyke, Lawrence W.; Loudon, Peter T.; Krishna, Ganesh; Clevenbergh, Philippe; Hernández-Mora, Miguel Górgolas; Herreros, José Miguel Cisneros; Albertson, Timothy E; Dougan, Michael; Thacker, Arthur A.; Baniecki, Mary Lynn; Soares, Holly; Whitlock, Mark; Nucci, Gianluca; Menon, Sandeep; Anderson, Annaliesa S.; Binks, Michael

doi:10.1093/ofid/ofad355

Cited by 4 publications

(1 citation statement)

References 20 publications

(20 reference statements)

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“…275 In 2020, the corresponding phosphate prodrug PF-07304814/lufotrelvir ( 63 ) was then developed by Pfizer to fight COVID-19 infection, 205,276 and this intravenous prodrug 207 underwent successful phase 1 clinical trials. 277,278 However, an additional trial (NCT05780541) was suspended by the FDA and lufotrelvir ( 63 ) was then withdrawn. More recent work borrowed the cyclohexane and the indole elements of 62 and led to aldehyde 64a or to the benzyl-bearing analogues 65 and 66 .…”

Section: Inhibitors Of the Sars-cov-2 Main Proteasementioning

confidence: 99%

On the origins of SARS-CoV-2 main protease inhibitors

Janin

2024

RSC Med. Chem.

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Section: Inhibitors Of the Sars-cov-2 Main Proteasementioning

confidence: 99%

On the origins of SARS-CoV-2 main protease inhibitors

Janin

2024

RSC Med. Chem.

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3-chymotrypsin-like protease in SARS-CoV-2

Al Adem,

Ferreira,

Villanueva

et al. 2024

Bioscience Reports

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Coronaviruses constitute a significant threat to the human population. Severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, is a highly pathogenic human coronavirus that has caused the COVID-19 pandemic. It has led to a global viral outbreak with an exceptional spread and a high death toll, highlighting the need for effective antiviral strategies. 3-chymotrypsin-like protease (3CLpro), the main protease in SARS-CoV-2, plays an indispensable role in the SARS-CoV-2 viral life cycle by cleaving the viral polyprotein to produce eleven individual non-structural proteins necessary for viral replication. 3CLpro is one of two proteases that function to produce new viral particles. It is a highly conserved cysteine protease with identical structural folds in all known human coronaviruses. Inhibitors binding with high affinity to 3CLpro will prevent the cleavage of viral polyproteins, thus impeding viral replication. Multiple strategies have been implemented to screen for inhibitors against 3CLpro, including peptide-like and small molecule inhibitors that covalently and non-covalently bind the active site, respectively. In addition, allosteric sites of 3CLpro have been identified to screen for small molecules that could make non-competitive inhibitors of 3CLpro. In essence, this review serves as a comprehensive guide to understanding the structural intricacies and functional dynamics of 3CLpro, emphasizing key findings that elucidate its role as the main protease of SARS-CoV-2. Notably, the review is a critical resource in recognizing the advancements in identifying and developing 3CLpro inhibitors as effective antiviral strategies against COVID-19, some of which are already approved for clinical use in COVID-19 patients.

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Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives

Khan,

Sathish,

Rohde

2024

J. Toxicol. Sci.

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The development and regulatory review of BNT162b2, a COVID-19 vaccine, and Paxlovid TM (nirmatrelvir tablets/ritonavir tablets), a COVID-19 therapeutic, are benchmarks for accelerated innovation during a global pandemic. Rapid choice of the SARS-CoV-2 spike protein and main protease (Mpro) as targets for the vaccine and therapeutic, respectively, leveraged the available knowledge of the biology of SARS-CoV-2 and related viruses. The nonclinical immunogenicity and safety of BNT162b2 was rigorously assessed. Likewise, a comprehensive nonclinical safety assessment was conducted for the therapeutic candidates, lufotrelvir (PF-07304814) and nirmatrelvir (PF-07321332). The development and regulatory review of BNT162b2 and Paxlovid was enabled through close collaboration of the pharmaceutical industry with regulatory agencies and public health organizations. This experience highlights approaches that could be adopted for pandemic preparedness including risk-based investment strategies, conduct of activities in parallel that normally are conducted sequentially, quick kill decisions, simultaneous evaluation of multiple candidates, and use of flexible, established vaccine platforms.

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Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19

Cited by 4 publications

References 20 publications

On the origins of SARS-CoV-2 main protease inhibitors

On the origins of SARS-CoV-2 main protease inhibitors

3-chymotrypsin-like protease in SARS-CoV-2

Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives

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