Broad-Spectrum Antiviral Agents against SARS-CoV-2 Variants Inhibit the Conserved Viral Protein Nsp1-RNA Interaction.

The ongoing global threats posed by COVID-19 pandemic, catalyzed by SARS-CoV-2, underscores the pressing need for effective antiviral strategies. The viral non-structural protein 1 (Nsp1) significantly influences pathogenicity by impeding host protein expression and enhancing viral RNA translation through its interaction with the stem-loop 1 (SL1) in the 5' untranslated region (UTR). We have developed a novel dual-luciferase reporter assay, designed to investigate the critical Nsp1-SL1 interaction, and identified P23E02 as a potential inhibitor. Our investigation, combining molecular docking studies and alanine mutagenesis, has unveiled that P23E02 disrupts Nsp1-40S ribosomal subunit interaction, liberating translational inhibition and empowering host antiviral responses. P23E02 exhibits antiviral efficacy against various sarbecoviruses, making it a promising candidate for combatting COVID-19 and related diseases. This study underscores the therapeutic potential of targeting the Nsp1/SL1 axis and lays the foundation for innovative antiviral interventions, ultimately fortifying global preparedness against future viral threats.

Unveiled reactivity of masked diformylmethane with enamines forming resonance-assisted hydrogen bonding leads to di-meta-substituted pyridines.

Pyridine, an essential structure in drug development, shows a wide array of bioactivities according to its substitution patterns. Among the bioactive pyridines, meta-substituted pyridines suffer from limited synthetic approaches despite their significance. In this study, we present a condensation-based synthetic method enabling the facile incorporation of biologically relevant functional groups at the meta position of pyridine. This methodology unveiled the concealed reactivity of 3-formyl(aza)indoles as diformylmethane analogs for synthesizing dissymmetric di-meta-substituted pyridines without ortho and para substitutions. Furthermore, we uncovered resonance-assisted hydrogen bonding (RAHB) as the requirement for the in situ generation of enamines, the key intermediates of this transformation. Successful development of the designed methodology linked to wide applications-core remodeling of natural products, drug-natural product conjugation, late-stage functionalization of drug molecules, and synthesis of the regioisomeric CZC24832. Furthermore, we discovered anti-inflammatory agents through the functional evaluation of synthesized bi-heteroaryl analogs, signifying the utility of this methodology.

Synthesis of substituted pyridines with diverse functional groups via the remodeling of (Aza)indole/Benzofuran skeletons.

Substituted pyridines with diverse functional groups are important structural motifs found in numerous bioactive molecules. Several methodologies for the introduction of various bio-relevant functional groups to pyridine have been reported, but there is still a need for a single robust method allowing the selective introduction of multiple functional groups. This study reports a ring cleavage methodology reaction for the synthesis of 2-alkyl/aryl 3-electron-withdrawing groups (esters, sulfones, and phosphonates) 5-aminoaryl/phenol pyridines via the remodeling of 3-formyl (aza)indoles/benzofurans. Totally ninety-three 5-aminoaryl pyridines and thirty-three 5-phenol pyridines were synthesized showing the robustness of the developed methodology. The application of this methodology further provided a privileged pyridine scaffold containing biologically relevant molecules and direct drug/natural product conjugation with ethyl 2-methyl nicotinate.

Mental Health Disorders Associated with Sinonasal and Skull Base Malignancies: A Large Cohort Study.

Objective The main purpose of this article is to examine the prevalence, incidence, sociodemographic, and clinical characteristics of mental health disorders (MHDs) among patients with skull base malignancies. Design Retrospective cohort study. Settings/Participants Six-thousand seven-hundred sixty sinonasal/skull base cancer patients in the MarketScan database between 2005 and 2014. Main Outcome Measures Frequency of MHDs pre- and post-diagnosis in patients harboring sinonasal/skull base malignancies. Results A significant increase in MHDs was noted from pre- to post-cancer diagnosis (22 vs 31%, p < 0.0001). Despite an increase in the prevalence rate, the demographic profile of patients with MHDs post-diagnosis remained similar to pre-diagnosis. Those patients harboring MHDs were, however, more likely to be women (62.7 vs 47.4%), and carry a history of smoking (40.9 vs 26.3%) than those without MHDs. These comparisons were statistically significant ( p < 0.0001). Conclusion The prevalence of MHDs increases following a diagnosis of a sinonasal/skull base malignancy. Patients with MHDs were more likely to be women and smokers.

Association of Head and Neck Cancer With Mental Health Disorders in a Large Insurance Claims Database.

IMPORTANCE: Although a few studies have shown that mental health disorders (MHDs) are strongly associated with the 5-year survival and recurrence rates in patients with head and neck cancer (HNC), none have been replicated in a large-scale study. OBJECTIVE: To describe the prevalence of MHDs in patients with HNC and the potential associations with survival and recurrence using a large insurance claims database. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study assessed data queried from the MarketScan database from January 1, 2005, through December 31, 2014, for 52 641 patients with a diagnosis of HNC. To exclude patients with a preexisting HNC diagnosis or those with incomplete data, patients were included if they were in the database for at least 12 months before the index diagnosis and continuously enrolled. Data were analyzed from February 20, 2017, through January 22, 2019. MAIN OUTCOMES AND MEASURES: To compare the frequency of MHDs before and after diagnosis of HNC, χ2 tests for independence were used. Adjusted adds ratios (aORs) were obtained using multivariable logistic regression by comparing the prevalence of MHDs in patients with oral cavity cancer and those with other cancer sites in the head and neck. RESULTS: Among the 52 641 patients included in the analysis (mean [SD] age, 51.31 [9.79] years), men (58.5%), patients aged 55 to 64 years (46.6%), and those from the South (40.3%) were most commonly affected by HNC. Oral cavity cancers (40.4%) were the most common type, followed by cancers of the oropharynx (19.2%) and larynx (15.5%). Of the various cancer sites, the OR for MHD prevalence was significantly increased in patients with cancers of the trachea compared with the oral cavity (2.11; 95% CI, 1.87-2.38). The prevalence of MHDs in patients with HNC increased to 29.9% compared with 20.6% before the cancer diagnosis. Specifically, women (adjusted OR, 1.58; 95% CI, 1.49-1.67) and patients with a history of tobacco use (adjusted OR, 1.42; 95% CI, 1.34-1.50) and alcohol use (adjusted OR, 1.56; 95% CI, 1.38-1.76) had significantly higher odds of MHDs after the diagnosis of HNC. CONCLUSIONS AND RELEVANCE: Although the baseline MHD prevalence of 20.6% before the cancer diagnosis was close to the national average (17.9% according to the National Survey on Drug Use and Health), results of this study showed that it increased to 29.9% after the cancer diagnosis. Women and patients with a history of tobacco and alcohol use were most susceptible to being diagnosed with an MHD. There is an association between patients with HNC and an increased prevalence of MHDs after treatment compared with the general population.

Atypical case of mucous membrane pemphigoid in a 26-year-old man.

A 26-year-old Caucasian man with no previous history of chemical injury presenting with an inability to open his right eye was investigated for mucous membrane pemphigoid and treated. Examination was notable for symblepharon of the right eye and impetigo-like lesions on the face and neck. A biopsy with immunohistochemical analysis was significant for linear deposits of C3 and immunoglobulin G at the level of the epithelial basement membrane, confirming the diagnosis of mucous membrane pemphigoid. Although mucous membrane pemphigoid classically presents bilaterally in women in the sixth and seventh decades of life, our patient was a young man with unilateral cicatrising conjunctivitis who may have been easily misdiagnosed without a high index of suspicion. A biopsy is required in cases of cicatrising conjunctivitis so that even atypical cases such as the one presented herein can be appropriately managed.