Clinical application of SARS-CoV-2 antibody detection and monoclonal antibody therapies against COVID-19.

The purpose of this study was to investigate the clinical application of severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) specific antibody detection and anti-SARS-CoV-2 specific monoclonal antibodies (mAbs) in the treatment of coronavirus infectious disease 2019 (COVID-19). The dynamic changes of SARS-CoV-2 specific antibodies during COVID-19 were studied. Immunoglobulin M (IgM) appeared earlier and lasted for a short time, while immunoglobulin G (IgG) appeared later and lasted longer. IgM tests can be used for early diagnosis of COVID-19, and IgG tests can be used for late diagnosis of COVID-19 and identification of asymptomatic infected persons. The combination of antibody testing and nucleic acid testing, which complement each other, can improve the diagnosis rate of COVID-19. Monoclonal anti-SARS-CoV-2 specific antibodies can be used to treat hospitalized severe and critically ill patients and non-hospitalized mild to moderate COVID-19 patients. COVID-19 convalescent plasma, highly concentrated immunoglobulin, and anti-SARS-CoV-2 specific mAbs are examples of anti-SARS-CoV-2 antibody products. Due to the continuous emergence of mutated strains of the novel coronavirus, especially omicron, its immune escape ability and infectivity are enhanced, making the effects of authorized products reduced or invalid. Therefore, the optimal application of anti-SARS-CoV-2 antibody products (especially anti-SARS-CoV-2 specific mAbs) is more effective in the treatment of COVID-19 and more conducive to patient recovery.

Synthesis of maleimide-braced peptide macrocycles and their potential anti-SARS-CoV-2 mechanisms.

Macrocycles often exhibit good biological properties and potential druggability, which lead to versatile applications in the pharmaceutical industry. Herein, we report a highly efficient and practical methodology for the functionalization and macrocyclization of Trp and Trp-containing peptides via Pd(II)-catalyzed C-H alkenylation at the Trp C4 position. This method provides direct access to C4 maleimide-decorated Trp-containing peptidomimetics and maleimide-braced 17- to 30-membered peptide macrocycles. In particular, these unique macrocycles revealed low micro- to sub-micromolar EC50 values with promising anti-SARS-CoV-2 activities. Further explorations with computational methodologies and experimental validations indicated that these macrocycles exert antiviral effects through binding with the N protein of SARS-CoV-2.

In vitro and in vivo evaluation of the main protease inhibitor FB2001 against SARS-CoV-2.

FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC50 = 0.39 ± 0.01 µM, EC90 = 0.75 ± 0.01 µM; B.1.351 (Beta): EC50 = 0.28 ± 0.11 µM, EC90 = 0.57 ± 0.21 µM; B.1.617.2 (Delta): EC50 = 0.27 ± 0.05 µM, EC90 = 0.81 ± 0.20 µM; B.1.1.529 (Omicron): EC50 = 0.26 ± 0.06 µM and EC50 = 0.042 ± 0.007 µM (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 replication in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed Ctrough ss in plasma and predicted Ctrough ss of lung total concentration were 0.163 and 2.5 µg/mL, which were approximately 9 and 132-fold higher than the EC50 of 0.019 µg/mL (0.042 µM) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934).

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.