Advances and challenges in using nirmatrelvir and its derivatives against SARS-CoV-2 infection

Chen, Wujun; Liang, Bing; Wu, Xiaolin; Li, Ling; Wang, Chao; Xing, Dongming

doi:10.1016/j.jpha.2022.10.005

Cited by 20 publications

(22 citation statements)

References 61 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Substantial evidence supports antiviral therapy in the form of paxlovid (ritonavir-boosted nirmatrelvir) and veklury (remdesivir) for patients with a high risk of progression to severe illness caused by COVID-19 [ 91 , 92 , 93 ]. These high-risk populations include patients over the age of 50 years, unvaccinated patients, and patients with specific medical conditions such as CVD, DM, or obesity [ 94 , 95 ].…”

Section: Treatment Management and Prevention Of Covid-19mentioning

confidence: 99%

COVID-19 Associated Cardiovascular Disease—Risks, Prevention and Management: Heart at Risk Due to COVID-19

Kemerley,

Gupta,

Thirunavukkarasu

et al. 2024

CIMB

View full text Add to dashboard Cite

The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) virus and the resulting COVID-19 pandemic have had devastating and lasting impact on the global population. Although the main target of the disease is the respiratory tract, clinical outcomes, and research have also shown significant effects of infection on other organ systems. Of interest in this review is the effect of the virus on the cardiovascular system. Complications, including hyperinflammatory syndrome, myocarditis, and cardiac failure, have been documented in the context of COVID-19 infection. These complications ultimately contribute to worse patient outcomes, especially in patients with pre-existing conditions such as hypertension, diabetes, or cardiovascular disease (CVD). Importantly and interestingly, reports have demonstrated that COVID-19 also causes myocardial injury in adults without pre-existing conditions and contributes to systemic complications in pediatric populations, such as the development of multisystem inflammatory syndrome in children (MIS-C). Although there is still a debate over the exact mechanisms by which such complications arise, understanding the potential paths by which the virus can influence the cardiovascular system to create an inflammatory environment may clarify how SARS-CoV-2 interacts with human physiology. In addition to describing the mechanisms of disease propagation and patient presentation, this review discusses the diagnostic findings and treatment strategies and the evolution of management for patients presenting with cardiovascular complications, focusing on disease treatment and prevention.

show abstract

Section: Treatment Management and Prevention Of Covid-19mentioning

confidence: 99%

COVID-19 Associated Cardiovascular Disease—Risks, Prevention and Management: Heart at Risk Due to COVID-19

Kemerley,

Gupta,

Thirunavukkarasu

et al. 2024

CIMB

View full text Add to dashboard Cite

show abstract

“…For example, patients presenting mild to moderate COVID-19 symptoms are treated with Paxlovid, which features the viral 3C-like protease inhibitor nirmatrelvir boosted by ritonavir, an inhibitor of cytochrome P450 CYP3A4 to prolong activity ( Shah et al, 2022 ). Paxlovid should however be initiated within 5 days of onset of symptoms in patients at risk of progressing to a severe state, but not to those requiring hospitalization due to severe COVID-19 ( Komorowski et al, 2022 ) nor to those with severe hepatic impairment ( Chaplin, 2022 ; Chen et al, 2023 ). Anti-inflammatory therapy includes timely administration of steroidal and nonsteroidal agents such as dexamethasone which, despite reducing mortality by ∼30% in ventilated patients, was associated with severe side effects ( Noreen et al, 2021 ) and with worsened clinical outcomes ( De Stefano et al, 2020 ; Noreen et al, 2021 ).…”

Section: Current Therapies For Sars-cov-2-infected Patientsmentioning

confidence: 99%

Pharmacological targeting of the hyper-inflammatory response to SARS-CoV-2-infected K18-hACE2 mice using a cluster of differentiation 36 receptor modulator

Gauvin,

Huynh,

Dubuc

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

The scientific and medical community faced an unprecedented global health hazard that led to nearly 7 million deaths attributable to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In spite of the development of efficient vaccines against SARS-CoV-2, many people remain at risk of developing severe symptoms as the virus continues to spread without beneficial patient therapy. The hyper-inflammatory response to SARS-CoV-2 infection progressing to acute respiratory distress syndrome remains an unmet medical need for improving patient care. The viral infection stimulates alveolar macrophages to adopt an inflammatory phenotype regulated, at least in part, by the cluster of differentiation 36 receptor (CD36) to produce unrestrained inflammatory cytokine secretions. We suggest herein that the modulation of the macrophage response using the synthetic CD36 ligand hexarelin offers potential as therapy for halting respiratory failure in SARS-CoV-2-infected patients.

show abstract

“…Ritonavir acts by decreasing the metabolism of Nirmatrelvir, decreasing the expression of CYP3A4 and consequently improving the efficacy of Nirmatrelvir [95]. Furthermore, Ritonavir has a high binding affinity to plasma proteins, suggesting that the increased action of Paxlovid may also be related to the efficacy of this drug [96]. When combined, Ritonavir may occupy the binding sites of these proteins in blood plasma, increasing the free concentration of Nirmatrelvir to have its antiviral action [96].…”

Section: Pre-clinical and Clinical Trials Of Reversible And Irreversi...mentioning

confidence: 99%

3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

Amorim,

Soares,

Ferrari

et al. 2024

Preprint

View full text Add to dashboard Cite

Proteases represent common targets in combating infectious diseases including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19 and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies unveil a proposal of a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.

show abstract

Advances and challenges in using nirmatrelvir and its derivatives against SARS-CoV-2 infection

Cited by 20 publications

References 61 publications

COVID-19 Associated Cardiovascular Disease—Risks, Prevention and Management: Heart at Risk Due to COVID-19

COVID-19 Associated Cardiovascular Disease—Risks, Prevention and Management: Heart at Risk Due to COVID-19

Pharmacological targeting of the hyper-inflammatory response to SARS-CoV-2-infected K18-hACE2 mice using a cluster of differentiation 36 receptor modulator

3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

Contact Info

Product

Resources

About