The rapid development of a vaccine is critical to the ongoing fight against COVID-19. However, there are always challenges, such as the constant emergence of new variants. Therefore, developing antiviral therapies is also an important approach to addressing the ongoing threat of COVID-19. Pfizer's Paxlovid (Paxlovid) oral drug for the new crown will be launched for the first time at the end of 2021. Until February this year, the official website of China's State Food and Drug Administration released the important news of the drug's import registration, which will be included in the medical insurance payment system shortly. The time was sensational.
It is worth mentioning that, for the preclinical research and development of anti-COVID-19 drugs, on one hand, Medicilon has already established a complete mRNA vaccine bioanalysis technology platform; It can provide professional pre-prescription services and lead compounds into late-stage development. Medicilon's pre-prescription research team has extensive experience in researching and developing various compounds, helping customers to advance the early screening of compounds successfully.
Medicilon can undertake the synthesis of special reagents, intermediates and molecular fragments, preparation of standard products, synthesis design and preparation of impurities or metabolites, synthesis of stable isotope internal standards and synthesis of tritiated compounds.
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The Special Effects Channel Leading to the Fight Against the New Crown - Paxlovid
The global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a global pandemic for over three years. Patients with COVID-19 exhibit a wide range of symptoms as the disease progresses. Common mild-to-moderate symptoms include fever, dry cough, fatigue, loss of smell, and diarrhea. Patients may develop pulmonary symptoms such as acute respiratory distress syndrome in severe and critical moments. Patients with pre-existing conditions such as hypertension, obesity, and diabetes show a higher risk of disease progression and lower survival rates. Men infected with COVID-19 have lower immunity and higher mortality than women. This may be due to sex-determining gene expression, chromosomes, and hormones. When COVID-19 progressed to a severe stage, the levels of inflammation-related factors in plasma increased significantly, including IL-1, IL-6, IL-7, G-CSF, IP-10, MCP1, MIP1α, and TNFα, thereby leading to a cytokine storm. Studies have shown that cytokine storms are directly associated with lung injury, multi-organ failure, and poor prognosis in severe COVID-19 cases.
COVID-19 therapies at different stages[1]
Progress in research and development of new crown oral drugs
Vaccines and oral treatments for COVID-19 are important methods to deal with COVID-19, and they are also powerful weapons to reduce deaths from COVID-19 infection. The currently verified targets are mainly 3CL protease (3CLpro) and RNA polymerase (RdRp). Among the popular 3CL protease inhibitors are Pfizer's Paxlovid, Shionogi's S-217622, etc.
Paxlovid
Paxlovid, Pfizer's oral small-molecule COVID-19 treatment, is administered in a combination pack of two tablets of Nirmatrelvir (PF-07321332) and one tablet of Ritonavir. Oral Paxlovid reduces hospitalization and mortality by ~90%.
Nirmatrelvir (PF-07321332) is a 3CL protease (3CLpro) inhibitor that inhibits SARS-CoV-2 proteins to prevent viral replication. Ritonavir is a cytochrome enzyme CYP3A4 inhibitor that reduces the metabolism of PF-07321332, allowing PF-07321332 to remain in the body longer at higher concentrations, increasing its therapeutic concentration.
Paxlovid can be used to treat mild and common adults within five days of onset and with high-risk factors for developing severe disease, and adolescents over 12 years old with a body weight greater than 40kg (the National Health and Medical Commission of China has adjusted the population to be used only for adults). For adults, the five related indicators include progressive aggravation of hypoxemia or respiratory distress, deterioration of tissue oxygenation indicators or increased lactic acid, and chest imaging showing the significant progression of lung lesions. For children, there are six indicators, including increased respiratory rate, poor mental response, lethargy, and underlying diseases.
Paxlovid's rapid advance
March 13, 2020, Dafydd R Owen et al. Initiate Protease Inhibitor Project
On July 22, 2020, Nirmatrelvir (PF-07321332) was synthesized for the first time.
On March 23, 2021, the Phase I clinical trial was initiated
On September 2, 2021, Phase II/III clinical trials will be initiated.
On December 9, 2021, Phase III clinical trials will be completed.
On December 22, 2021, FDA emergency approval
February 11, 2022, NMPA emergency approval
On March 9, 2022, the commercial agreement was signed.
On March 15, 2022, the National Health and Medical Commission added it to the "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Ninth Edition)."
In the middle of the night on March 16, 2022, 20,000 boxes arrived at Pudong Airport.
On March 18, 2022, customs clearance will be completed in two hours.
Arrived in Changchun on March 20, 2022, and immediately sent to the frontline of the anti-epidemic
On March 22, 2022, the National Medical Insurance Bureau will include Pfizer's new crown oral medicine in the scope of medical insurance payment.
3CL protease
SARS-CoV-2 produces two polyproteins, pp1a, and pp1ab, which are processed by two virally encoded cysteine proteases, the main proteases being 3CL protease (3CLpro) and papain-like protease. Mutagenesis experiments with other coronaviruses have shown that the activity of 3CLpro is critical for viral replication. 3CLpro proteolytically processes viral p1a/p1ab proteins at more than ten junctions to generate a series of nonstructural proteins critical for viral replication and transcription, including RdRp, helicase, and 3CLpro itself. The fundamental functional importance of proteases in viral replication has led to the clinical success of protease inhibitors against a wide variety of viruses. Making 3CLpro an attractive antiviral drug target.
Nirmatrelvir (PF-07321332)
Nirmatrelvir (PF-07321332) is a 3CLpro inhibitor with potent in vitro antiviral activity against SARS-CoV-2 and other coronaviruses. The binding mechanism of PF-07321332 to coronavirus 3CLpro was demonstrated by docking and molecular dynamics simulations. Investigating the dynamic behavior of ligand-protein interactions found that PF-07321332 exhibited stronger binding by interacting with the catalytic binary residues His41-Cys145 of 3CLpro. This research will help develop and optimize more specific compounds to fight the coronavirus disease.
Dafydd R Owen et al. report the discovery and characterization of PF-07321332, which targets a significant protease involved in polyprotein cleavage of viral replication. PF-07321332 is an orally bioavailable SARS-CoV-2 major protease inhibitor with in vitro antiviral activity, excellent off-target selectivity, and in vivo safety. PF-07321332 is orally administered, has good selectivity and safety, and protects against infection in mouse models. In Phase, I clinical trials, in vitro results showed that PF-07321332 reached the concentration expected to inhibit the virus. PF-07321332 also inhibits other coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-COV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), and could serve as an arsenal against future viral threats.
PF-07321332 effectively reduces SARS-CoV-2 MA10 viral load in mouse lungs. The researchers evaluated the in vivo antiviral effect of PF-07321332 in the mouse SARS-CoV-2 MA10 model. Intranasal infection of BALB/c mice with SARS-CoV-2 MA10 resulted in ~10% body weight loss in 10-week-old mice. After infection with SARS-CoV-2 MA10, mice treated with PF-07321332 (at doses of 300 and 1000 mg/kg twice daily) lost weight compared to control mice. Mice were sacrificed four days after infection, and lung virus titers were assessed by CCID50 assay. Infected animals in the control group had an intense lung illness (mean titer log10 4.93±0.140 CCID50/mL SARS-CoV-2 MA10). In contrast, mice treated with PF-07321332 had significantly lower virus levels (300 and 1000 mg /kg PF-07321332-treated groups had mean viral titers of log10 3.53±0.187 log10 3.02±0.423 CCID50/mL, respectively).
PF-07321332 is effective in animal models[2]
Summary and Outlook
As a new oral drug for treating new coronary pneumonia, Paxlovid has performed well in clinical research, reducing the risk of hospitalization or death of patients with recent coronary pneumonia by ~90%—strategies for treatment. China has conditionally approved the import registration of Paxlovid as a drug that can change the prevention and control strategy of the new crown pneumonia epidemic.
The novel coronavirus pneumonia outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has brought unprecedented threats to human health and sounded the alarm for the world. In addition to vaccines, antiviral therapies are an essential part of the healthcare response to the ongoing threat of COVID-19. For active pharmaceutical ingredients or druggable candidate compounds, Medicilon can provide professional pre-prescription services and lead the compounds into late-stage development. Medicilon's pre-prescription research team has extensive experience in researching and developing various combinations, helping customers to advance the early screening of compounds successfully.
References:
[1] Jieya Wu, et al. Prospective: Evolution of Chinese Medicine to Treat COVID-19 Patients in China. Front Pharmacol. 2021 Feb25;11:615287.
[2] Dafydd R Owen, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021 Dec24;374(6575):1586-1593.
[3] Bilal Ahmad, et al. Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations. Int J Mol Sci. 2021 Aug24;22(17):9124.
[4] Britton Boras, et al. Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nat Commun. 2021 Oct18;12(1):6055.
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