A series of nonpeptide benzamide-containing inhibitors of human rhinovirus (HRV) 3C protease was identified using structure-based design. The design, synthesis, and biological evaluation of these inhibitors are reported. A Michael acceptor was combined with a benzamide core mimicking the P1 recognition element of the natural 3CP substrate. R,β-Unsaturated cinnamate esters irreversibly inhibited the 3CP and displayed antiviral activity (EC 50 0.60 µM, HRV-16 infected H1-HeLa cells). On the basis of cocrystal structure information, a library of substituted benzamide derivatives was prepared using parallel synthesis on solid support. A 1.9 Å cocrystal structure of a benzamide inhibitor in complex with the 3CP revealed a binding mode similar to that initially modeled wherein covalent attachment of the nucleophilic cysteine residue is observed. Unsaturated ketones displayed potent reversible inhibition but were inactive in the cellular antiviral assay and were found to react with nucleophilic thiols such as DTT.
BACKGROUND: Probe-based confocal laser endomicroscopy (pCLE) is an emerging method for in-vivo imaging of the gastrointestinal tract and requires a contrast agent. Fluorescein is the most commonly used agent. The optimal dose of fluorescein for pCLE in colon is unknown. OBJECTIVE: Exploration of optimal dose of fluorescein for pCLE in colon. DESIGN: Comparative, prospective pilot trail. SETTING: Tertiary-care center. PATIENTS: 18 participants underwent colonoscopy without complications. INTERVENTIONS: pCLE videos were recorded in normal cecum, using 10% fluorescein intravenously. MAIN OUTCOME MEASUREMENTS: For subjective analysis, pCLE videos were scored for quality, by 2 observers, independently and blinded to fluorescein dose. For objective analysis, signal-to-noise ratios (SNR) were calculated for each video by an expert. RESULTS: 6 fluorescein doses were used, including 0.5 mL, 1 mL, 2.5 mL, 5 mL, 7.5 mL and 10 mL and each dose was used in three patients. For each dose, median image quality score was 2.5, 2.0, 3.25, 4.0, 4.0 and 3.5 by first observer and 2.0, 3.0, 4.0, 5.0, 4.0 and 4.0 by second observer, respectively. The subjective quality scores increased from 0.5 mL to 5.0 mL, with no evidence of further improved quality at 7.5 mL and 10 mL doses. SNR were not significantly different between doses but trended higher for higher doses. LIMITATIONS: Small sample size. The results can not be applied to other parts of gastrointestinal tract i.e. duodenum, esophagus with different blood supply. CONCLUSION: This preliminary study suggests that the optimal dose of fluorescein for high quality pCLE imaging in colon is approximately 5.0 mL.
In participants with IPMN-Br, short-term follow-up after solid organ transplant was not associated with any significant change in cyst characteristics suggesting that incidental IPMN-Br, even in the setting of immunosuppression post-transplant, can be followed conservatively.
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