Structure-Guided Design of Conformationally-Constrained Cyclohexane Inhibitors of SARS-CoV-2 3CL Protease

A series of non-deuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally-constrained cyclohexane moiety was synthesized and found to potently inhibit SARS-CoV-2 3CL protease in biochemical and cell-based assays

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies.

We describe herein the results of our studies related to the application of X-ray crystallography, the Thorpe-Ingold effect, deuteration, and stereochemistry in the design of highly potent and non-toxic inhibitors of SARS-CoV-2 3CLpro to combat SARS-CoV-2 and emerging variants.</p

Potent 3CLpro inhibitors effective against SARS-CoV-2 and MERS-CoV in animal models by therapeutic treatment

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic betacoronaviruses that continue to have a significant impact on public health. Timely development and introduction of vaccines and antivirals against SARS-CoV-2 into the clinic have substantially mitigated the burden of COVID-19. However, a limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections, respectively, calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. In this report, we examined the efficacy of two potent 3CLpro inhibitors, 5d and 11d, in fatal animal models of SARS-CoV-2 and MERS-CoV to demonstrate their broad-spectrum activity against both viral infections. These compounds significantly increased the survival of mice in both models when treatment started 1 day post infection compared to no treatment which led to 100% fatality. Especially, the treatment with compound 11d resulted in 80% and 90% survival in SARS-CoV-2 and MERS-CoV-infected mice, respectively. Amelioration of lung viral load and histopathological changes in treated mice correlated well with improved survival in both infection models. Furthermore, compound 11d exhibited significant antiviral activities in K18-hACE2 mice infected with SARS-CoV-2 Omicron subvariant XBB.1.16. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses.IMPORTANCEHuman coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) continue to have a significant impact on public health. A limited or lacking therapeutic arsenal for SARS-CoV-2 and MERS-CoV infections calls for an expanded and diversified portfolio of antivirals against these coronavirus infections. We have previously reported a series of small-molecule 3C-like protease (3CLpro) inhibitors against human coronaviruses. In this report, we demonstrated the in vivo efficacy of 3CLpro inhibitors for their broad-spectrum activity against both SARS-CoV-2 and MERS-CoV infections using the fatal animal models. The results suggest that these are promising candidates for further development as broad-spectrum direct-acting antivirals against highly virulent human coronaviruses

Bleeding Complications Drive In-Hospital Mortality of Patients with Atrial Fibrillation after Transcatheter Aortic Valve Replacement

Background Atrial fibrillation (AF) is a risk factor for poor postoperative outcome after transfemoral transcatheter aortic valve replacement (TF-TAVR). The present study analyses the outcomes after TF-TAVR in patients with or without AF and identifies independent predictors for in-hospital mortality in clinical practice. Methods and Results Among all 57,050 patients undergoing isolated TF-TAVR between 2008 and 2016 in Germany, 44.2% of patients (n = 25,309) had AF. Patients with AF were at higher risk for unfavorable in-hospital outcome after TAVR. Including all baseline characteristics for a risk-adjusted comparison, AF was an independent risk factor for in-hospital mortality after TAVR. Among patients with AF, EuroSCORE, New York Heart Association classification class, or renal disease had only moderate effects on mortality, while the occurrence of postprocedural stroke or moderate to major bleeding substantially increased in-hospital mortality (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.61-4.30,p < 0.001 and OR 3.12, 95% CI 2.68-3.62,p < 0.001). However, the strongest independent predictor for in-hospital mortality among patients with AF was severe bleeding (OR 18.00, 95% CI 15.22-21.30,p < 0.001). Conclusion The present study demonstrates that the incidence of bleeding defines the in-hospital outcome of patients with AF after TF-TAVR. Thus, the periprocedural phase demands particular care in bleeding prevention

Very early infective endocarditis after transcatheter aortic valve replacement

International audienceBackground Scarce data exist about early infective endocarditis (IE) after trans-catheter aortic valve replacement (TAVR). Objective The objective was to evaluate the characteristics, management, and outcomes of very early (VE) IE (&lt;= 30 days) after TAVR. Methods This multicenter study included a total of 579 patients from the Infectious Endocarditis after TAVR International Registry who had the diagnosis of definite IE following TAVR. Results Ninety-one patients (15.7%) had VE-IE. Factors associated with VE-IE (vs. delayed IE (D-IE)) were female gender (p = 0.047), the use of self-expanding valves (p &lt; 0.001), stroke (p = 0.019), and sepsis (p &lt; 0.001) after TAVR. Staphylococcus aureus was the main pathogen among VE-IE patients (35.2% vs. 22.7% in the D-IE group, p = 0.012), and 31.2% of Staphylococcus aureus infections in the VE-IE group were methicillin-resistant (vs. 14.3% in the D-IE group, p = 0.001). The second-most common germ was enterococci (34.1% vs. 24.4% in D-IE cases, p = 0.05). VE-IE was associated with very high in-hospital (44%) and 1-year (54%) mortality rates. Acute renal failure following TAVR (p = 0.001) and the presence of a non-enterococci pathogen (p &lt; 0.001) were associated with an increased risk of death. Conclusion A significant proportion of IE episodes following TAVR occurs within a few weeks following the procedure and are associated with dismal outcomes. Some baseline and TAVR procedural factors were associated with VE-IE, and Staphylococcus aureus and enterococci were the main causative pathogens. These results may help to select the more appropriate antibiotic prophylaxis in TAVR procedures and guide the initial antibiotic therapy in those cases with a clinical suspicion of IE