Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 268, P. 116202 - 116202

Published: Feb. 6, 2024

To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in field antiviral drug discovery is still infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum activity against coronaviruses. Here, report design, synthesis, characterization a novel series INM-based that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel was also enlarged by varying linker moiety. resulted very susceptible this modification, particularly for hijacking VHL as ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 infected human lung cells. Interestingly, assays both uninfected virus-infected cells most promising emerged so far (PROTACs 5 demonstrated INM-PROTACs do not degrade PGES-2 protein, initially hypothesized, but induce concentration-dependent SARS-CoV-2 main protease (Mpro) Mpro-transfected SARS-CoV-2-infected Importantly, thanks target degradation, exhibited considerable enhancement respect indomethacin, EC50 values low-micromolar/nanomolar range. Finally, kinetic solubility well metabolic chemical stability were measured 6. Altogether, identification first class Mpro degraders demonstrating represents significant advance development effective, anti-coronavirus strategies.

Language: Английский

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Real-World Effectiveness Study of Nirmatrelvir-Ritonavir or Molnupiravir in Hospitalized Unvaccinated Patients with Chronic Respiratory Diseases and Moderate COVID-19 at Presentation

International Journal of COPD, Journal Year: 2024, Volume and Issue: Volume 19, P. 77 - 86

Published: Jan. 1, 2024

Introduction: Nirmatrelvir-ritonavir (NMV-r) and molnupiravir (MOL) were developed as out-patient anti-viral for mild COVID-19. There was limited data on their role in treating COVID-19 hospitalized patients, especially among adult patients who are unvaccinated had chronic respiratory diseases. Methods: A territory-wide retrospective study conducted Hong Kong to compare the efficacy of NMV-r MOL against with asthma, obstructive pulmonary disease, bronchiectasis interstitial lung diseases presenting moderate from 16th February 2022 15th March 2023. Results: total 1354 included, 738 received 616 MOL. more effective reducing 90-day mortality adjusted hazard ratios (aHR) 0.508 (95% confidence interval [CI] = 0.314– 0.822, p 0.006). Patients also significantly shorter length stay (LOS) than those receiving MOL, median LOS 4 (Interquartile range [IQR] 2– 7) 6 (IQR 3– 10) (p-value < 0.001). no statistically significant difference development failure severe two groups. Discussion: adults without hypoxaemia admission. Keywords: COPD, bronchiectasis, molnupiravir, nirmatrelvir-ritonavir,

Language: Английский

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Clinical outcomes among COVID-19 patients initiated on molnupiravir in Denmark – A national registry study

Antiviral Therapy, Journal Year: 2025, Volume and Issue: 30(1)

Published: Jan. 21, 2025

Background Molnupiravir (MOV) is an orally bioavailable ribonucleoside with antiviral activity against all tested SARS-CoV-2 variants. We describe the demographic, clinical, and treatment characteristics of non-hospitalized Danish patients treated MOV their clinical outcomes following initiation. Method Among adults (>18 years) who received between 16 December 2021 30 April 2022 in outpatient setting Denmark, we summarized demographic at baseline post-MOV using descriptive statistics. Outcomes were emergent hospitalization all-cause mortality during 28 days after estimated odds ratios (OR) by time from positive test to logistic regression. Results identified 3691 MOV-treated patients, whom 45.8% male mean age was 70.1 years. Most (76.2%) initiated within 0–2 a 16.8% 3–5 days. Over 28-day period, rates for all-cause, respiratory- or COVID-19-related, COVID-19-related 4.8%, 2.6% 1.5%, respectively. All-cause 1.6%. Initiation compared 1–2 associated increased risk (OR 1.85, 95% CI 1.29–2.67) respiratory 1.78, 1.07–2.94) hospitalization, 2.90, 1.64–5.15). Conclusion primarily prescribed vaccinated elderly persons multiple comorbidities. The this population low. Early initiation reduced death late

Language: Английский

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Comparing Molnupiravir to Nirmatrelvir/Ritonavir (Paxlovid) in the Treatment of Mild-to-Moderate COVID-19 in Immunocompromised Cancer Patients

Cancers, Journal Year: 2024, Volume and Issue: 16(5), P. 1055 - 1055

Published: March 5, 2024

Nirmatrelvir/Ritonavir has been shown to reduce the risk of COVID-19 progression by 88% compared placebo, while Molnupiravir reduced it 31%. However, these two agents have not head-to-head. We therefore safety and efficacy both for treatment mild-to-moderate in immunocompromised cancer patients. identified 240 patients diagnosed with treated or Nirmatrelvir/Ritonavir. Patients were matched using a 1:2 ratio based on age group (18-64 years vs. ≥65) type cancer. The collected data included demographics, comorbidities, outcome. Both groups had comparable characteristics presenting symptoms. dyspnea was more prevalent group, sore throat group. rate disease univariate multivariable analysis. Treatment versus revealed no significant difference analysis (adjusted OR = 1.31, 95% CI: 0.56-3.14, p 0.70). who received Nirmatrelvir/Ritonavir, however, significantly prone having drug-drug interactions/adverse events (30% 0%, < 0.0001). In patients, preventing severe disease/death rebound events, superior profile.

Language: Английский

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Post-marketing surveillance study on the effectiveness and safety of molnupiravir in high-risk COVID-19 outpatients: a prospective case series study

Pharmacological Reports, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Language: Английский

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Effectiveness and Adverse Events of Nirmatrelvir/Ritonavir Versus Molnupiravir for COVID-19 in Outpatient Setting: Multicenter Prospective Observational Study

Journal of Korean Medical Science, Journal Year: 2023, Volume and Issue: 38(42)

Published: Jan. 1, 2023

In this study, we aimed to compare the effectiveness and adverse reactions of nirmatrelvir/ritonavir molnupiravir in high-risk outpatients with coronavirus disease 2019 (COVID-19).This multicenter prospective observational study evaluated rate hospitalization, death, events within 28 days oral antiviral agent prescription (molnupiravir, n = 240; nirmatrelvir/ritonavir, 240) 480 nonhospitalized adult patients COVID-19 from August 2, 2022 March 31, 2023.Patients receiving had a higher prevalence comorbidities (85.8% vs. 70.4%; P < 0.001) Charlson comorbidity index (2.8 ± 1.4 2.5 1.5; 0.009) than those nirmatrelvir/ritonavir. Three required hospitalization (nirmatrelvir/ritonavir group, 1 [0.4%]; 2 [0.8%]; 1.000). Nirmatrelvir/ritonavir was associated risk (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.27-3.03), especially for aged 65 years older (OR, 3.04; CI, 1.71-5.39). The severity both groups mild moderate improved after discontinuation medication. age ≥ 0.43 0.22-0.86) appropriate vaccination 0.37; 0.15-0.91) reduced occurrence events.The rates death were low not significantly different between who received either or molnupiravir. Although more frequent molnupiravir, none severe. can be safely used treat COVID-19, while could considered as an alternative treatment option groups.

Language: Английский

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Nirmatrelvir/ritonavir for the treatment of immunocompromised adult patients with early‐stage symptomatic COVID‐19: A real‐life experience

Journal of Medical Virology, Journal Year: 2023, Volume and Issue: 95(9)

Published: Sept. 1, 2023

Regardless of vaccination status, progression to severe coronavirus disease 2019 (COVID-19) is still a relevant cause morbidity among immunocompromised patients. Despite the proven efficacy nirmatrelvir/ritonavir (NMV/r), concerns remain regarding potential for drug-to-drug interactions (DDIs) and safety in this at-risk population. We aimed evaluate clinical outcomes patients treated with NMV/r, as well occurrence DDIs treatment-emergent adverse events (TEAEs). This retrospective observational study included all some form immunosuppression laboratory-confirmed COVID-19 that received NMV/r at our center from April August 2022. The main outcome was worsening status (increase ≥1 point baseline validated scale) by Days +7 +28 after initiation therapy. Safety rates any TEAE potentially DDIs. 110 Main causes were hematological malignancy (58.2%) (mainly multiple myeloma [22.7%] non-Hodgkin lymphoma [13.6%]), active chemotherapy (30.0%) hematopoietic stem cell transplantation (14.5%). Clinical observed four (3.6%) five (4.5%), respectively. Only one patient had positive SARS-CoV-2 polymerase chain reaction test Day +28. At least DDI 56.4% rate attributable TEAEs 10.9%, although only two (1.8%) required premature discontinuation NMV/r. Early therapy should be considered COVID-19, particular attention interacting medications.

Language: Английский

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Clinical Outcome and 7-Day Virological Clearance in High-Risk Patients with Mild–Moderate COVID-19 Treated with Molnupiravir, Nirmatrelvir/Ritonavir, or Remdesivir

Infectious Diseases and Therapy, Journal Year: 2024, Volume and Issue: 13(7), P. 1589 - 1605

Published: June 3, 2024

We compared the effectiveness and virological clearance (VC) at day 7 (T7) post-treatment with molnupiravir, nirmatrelvir/ritonavir, remdesivir in SARS-CoV-2-infected patients high risk (HR) for clinical progression. conducted a retrospective study enrolling HR mild-to-moderate COVID-19 (Jan-Oct 2022) treated nirmatrelvir/ritonavir or molnupiravir 3 days of remdesivir. investigated recovery T7 (resolution symptoms ≥ 72 h all-cause death), VC (PCR/antigenic negative nasopharyngeal swab), median time to (days from symptom onset first swab). Factors associated were by logistic regression. In study, 92/376 (43.8%) received 150/376 (24.7%) 134/376 (31.5%) Forty-nine (13%) unvaccinated incompletely vaccinated. Patients younger presented immunodeficiencies more frequently; was used commonly hospitalized other diseases. A proportion obtained without differences among therapies (97.5% 98.3% 93.6% remdesivir); 12 (3.7%) died. Nirmatrelvir/ritonavir higher shorter molnupiravir/remdesivir, also after adjustment age immunodeficiency (AOR 0.445 RDV vs. NMV-r, 95% CI 0.240-0.826, p = 0.010; AOR 0.222 MNP 0.105-0.472, < 0.001). SARS-COV-2 antiviral treatments are an excellent therapeutic strategy patients. showed as early treatment, confirming its likely superiority indirect comparisons.

Language: Английский

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Targeted degrader technologies as prospective SARS-CoV-2 therapies

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 29(1), P. 103847 - 103847

Published: Nov. 28, 2023

Language: Английский

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Prognostic improvement and treatment of COVID-19 in patients with rheumatic diseases until December 2022: Analysis of the JCR COVID-19 registry in Japan

Modern Rheumatology, Journal Year: 2023, Volume and Issue: 34(3), P. 576 - 583

Published: June 17, 2023

The aim is to evaluate the treatment and prognosis of coronavirus disease 2019 (COVID-19) according time onset dominant strain in patients with rheumatic diseases.

Language: Английский

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