Chemical Physics Letters, Journal Year: 2022, Volume and Issue: 794, P. 139489 - 139489
Published: Feb. 22, 2022
Language: Английский
Drugs, Journal Year: 2022, Volume and Issue: 82(5), P. 585 - 591
Published: March 19, 2022
Nirmatrelvir plus ritonavir (Paxlovid™; Pfizer) is a co-packaged combination of nirmatrelvir and tablets, intended for co-administration developed the treatment post-exposure prophylaxis coronavirus disease 2019 (COVID-19). peptidomimetic inhibitor severe acute respiratory syndrome 2 (SARS-CoV-2) main protease, while human immunodeficiency virus type 1 (HIV-1) protease CYP3A inhibitor. received its first conditional authorization in December 2021 United Kingdom, COVID-19 adults who do not require supplemental oxygen are at increased risk progression to COVID-19. In January 2022, EU use same indication. authorized emergency USA. This article summarizes milestones development leading authorizations approval
Language: Английский
Citations
245
BioMed Research International, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 16
Published: July 7, 2022
In this work, the discovery and description of PF-07321332, a major bioavailable oral SARS-CoV-2 protease inhibitor with in vitro human coronavirus antiviral activity, excellent selection off-target vivo immune profiles are reported. Various drugs novel compound candidates for treatment COVID-19 pandemic have been developed. PF-07321332 (or nirmatrelvir) is new drug developed by Pfizer. response to pandemic, Pfizer has COVID vaccine 2022 will launch its anti-SARS-Cov-2 (PI). The combination ritonavir nirmatrelvir under study phase III clinical trial brand name Paxlovid. Paxlovid an active 3Cl inhibitor. exerts efficacy inhibiting necessary viral replication procedure. Proteases cleave several sites polyprotein where pyrrolidone was replaced flexible glutamine. Due there high demand synthesis development drug. Herein, we report synthetic route mechanism action recently published on nirmatrelvir. Also, comparison performance two antiviruses (molnupiravir described. This review be helpful different disciplines such as biochemistry, organic chemistry, medicinal pharmacology.
Language: Английский
Citations
105
Medicinal Chemistry Research, Journal Year: 2022, Volume and Issue: 31(10), P. 1637 - 1646
Published: Aug. 30, 2022
Language: Английский
Citations
95
Antibiotics, Journal Year: 2022, Volume and Issue: 11(2), P. 220 - 220
Published: Feb. 9, 2022
Nirmatrelvir/ritonavir (Paxlovid™) is an effective and safe antiviral drug that inhibits the main protease (Mpro), 3CL protease, of SARS-CoV-2. A reduction in COVID-19-related hospitalization or death was observed patients treated with nirmatrelvir/ritonavir within five days symptom onset. Moreover, good oral availability enables usage nirmatrelvir/ritonavir, not only hospitalized patients, but also among outpatients. Nirmatrelvir (PF-07321332) has been demonstrated to stop spread COVID-19 animal models. Despite frequent mutations viral genomes SARS-CoV-2, nirmatrelvir shows effect against recent coronavirus mutants. promising nirmatrelvir, there are several unresolved concerns. First, final results large-scale clinical trials for early therapy mild cases yet published. Second, effectiveness upcoming variants coming years requires close monitoring. Considering preliminary EPIC-HR trial, conjunction vaccines non-pharmacological interventions, may represent dawn dark pandemic.
Language: Английский
Citations
89
International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 9866 - 9866
Published: Aug. 30, 2022
Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, treatment of HIV (e.g., lopinavir/ritonavir) more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its importance, exact mechanism ritonavir-mediated CYP3A4 inactivation still not fully understood. Nonetheless, ritonavir clearly mechanism-based inactivator, which irreversibly blocks CYP3A4. Here, we discuss four fundamentally different mechanisms proposed this irreversible inactivation/inhibition, namely (I) formation metabolic-intermediate complex (MIC), tightly coordinating heme group; (II) strong ligation unmodified iron; (III) destruction; (IV) covalent attachment reactive intermediate apoprotein. further appears inactivate CYP3A5 similar potency, important since patients all ethnicities. Although it currently possible conclude what primary action vivo is, unlikely that any are wrong. We, therefore, propose markedly inactivates CYP3A through mixed set mechanisms. This functional redundancy may well contribute overall inhibitory efficacy.
Language: Английский
Citations
71
Computational and Structural Biotechnology Journal, Journal Year: 2022, Volume and Issue: 20, P. 824 - 837
Published: Jan. 1, 2022
Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in late 2019, the coronavirus disease 2019 (COVID-19) pandemic has challenged public health around world. Currently, there is an urgent need to explore antiviral therapeutic targets and effective clinical drugs. In this study, we systematically summarized two main strategies against COVID-19, namely drugs targeting SARS-CoV-2 life cycle SARS-CoV-2-induced inflammation host cells. The development of above implemented by repurposing exploring potential targets. A comprehensive summary promising drugs, especially cytokine inhibitors, traditional Chinese medicine (TCM), provides recommendations for clinicians as evidence-based actual COVID-19 treatment. Considering emerging variants greatly impact effectiveness vaccines, reviewed appearance details further perspectives drug design, which brings updating clues develop therapeutical agents variants. Based on this, broadly combined with immunomodulatory, or holistic therapy host, prior being considered interventions mutant strains SARS-CoV-2. Therefore, it highly acclaimed requirements concerted efforts from multi-disciplinary basic studies trials, improves accurate treatment optimizes contingency measures
Language: Английский
Citations
65
International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(7), P. 3507 - 3507
Published: March 23, 2022
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of most devastating pandemics recent times. The lack potent novel antivirals had led to global health crises; however, emergence and approval inhibitors viral main protease (Mpro), such as Pfizer’s newly approved nirmatrelvir, offers hope not only in therapeutic front but also context prophylaxis against infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, lessons learnt from previous currently ongoing taught us that these can easily escape selection pressure through vital target amino acid residues monotherapeutic settings. In this paper, we review nirmatrelvir its binding SARS-CoV-2 Mpro draw a comparison HIV were rendered obsolete resistance mutations, emphasizing potential pitfalls design may be important relevance long-term use SARS-CoV-2.
Language: Английский
Citations
63
Revista Española de Quimioterapia, Journal Year: 2022, Volume and Issue: 35(3), P. 236 - 240
Published: Feb. 20, 2022
All coronavirus, including SARS-CoV-2, encode two proteases needed for the processing of PP1A and PP1AB polyproteins. The main protease 3CL (chemotripsine-like) gives rise to formation NSP11/16 proteins. has been constituted as one possible therapeutic targets development antiviral drugs against SARS-COV-2 due its highly conserved sequence structure among all coronaviruses. During SARS-COV-1 pandemic, a hydroxymethyl ketone derivative (PF-00835231) was identified with an intense inhibitory activity protease. Subsequent chemical modifications gave PF-07321332 (nirmatrelvir) which shown high efficacy SARS-COV-2. company's data indicate that it is capable reducing 89% risk hospitalization death patients infected hardly adverse effects. Its effectiveness improves if administered orally in first 24-48 hours duration treatment established between 3-5 days. commercial form associated ritonavir metabolism nirmatrelvir, lengthening average life. This would be effective current future viral variants, since not modified them. FDA approved this November 2021 EMA final evaluation phase.
Language: Английский
Citations
50
Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 797 - 797
Published: July 4, 2024
The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.
Language: Английский
Citations
9
mBio, Journal Year: 2022, Volume and Issue: 13(1)
Published: Feb. 15, 2022
The ongoing COVID-19 pandemic caused by SARS-CoV-2 has claimed over 5.5 million lives with more than 300 people infected worldwide. While vaccines are effective, the emergence of new viral variants could jeopardize vaccine protection.
Language: Английский
Citations
27