Discovery of C13-Aminobenzoyl Cycloheximide Derivatives that Potently Inhibit Translation Elongation.

Employed for over half a century to study protein synthesis, cycloheximide (CHX, 1) is a small molecule natural product that reversibly inhibits translation elongation. More recently, CHX has been applied to ribosome profiling, a method for mapping ribosome positions on mRNA genome-wide. Despite CHX's extensive use, CHX treatment often results in incomplete translation inhibition due to its rapid reversibility, prompting the need for improved reagents. Here, we report the concise synthesis of C13-amide-functionalized CHX derivatives with increased potencies toward protein synthesis inhibition. Cryogenic electron microscopy (cryo-EM) revealed that C13-aminobenzoyl CHX (8) occupies the same site as CHX, competing with the 3' end of E-site tRNA. We demonstrate that 8 is superior to CHX for ribosome profiling experiments, enabling more effective capture of ribosome conformations through sustained stabilization of polysomes. Our studies identify powerful chemical reagents to study protein synthesis and reveal the molecular basis of their enhanced potency.

Versatile Synthetic Route to Cycloheximide and Analogues That Potently Inhibit Translation Elongation.

Cycloheximide (CHX) is an inhibitor of eukaryotic translation elongation that has played an essential role in the study of protein synthesis. Despite its ubiquity, few studies have been directed towards accessing synthetic CHX derivatives, even though such efforts may lead to protein synthesis inhibitors with improved or alternate properties. Described here is the total synthesis of CHX and analogues, and the establishment of structure-activity relationships (SAR) responsible for translation inhibition. The SAR studies aided the design of more potent compounds, one of which irreversibly blocks ribosomal elongation, preserves polysome profiles, and may be a broadly useful tool for investigating protein synthesis.

Disaster Evacuation for Home-Based Patients with Special Healthcare Needs: A Cross-Sectional Study.

Recent super-typhoons and torrential rains triggered by global warming have had disproportionately large effects on medically vulnerable people in Japan. This study aimed to identify factors associated with intention to evacuate to the nearest public shelter among family caregivers of pediatric patients receiving home medical care. The study included family caregivers of these patients from the Department of Pediatrics, Fukuoka University Hospital, Japan, including family caregivers of young adults with special healthcare needs. An original questionnaire was prepared drawing on previous studies and used for an interview survey. Overall, 57 individuals provided valid data and were included in the analysis. Factors associated with evacuation intention were non-use of a home ventilator (odds ratio [OR] 3.99, 95% confidence interval [CI]: 1.13-14.03) and not having made arrangements to use a non-public shelter (OR 7.29 95% CI: 1.62-32.88). This means that those who use mechanical ventilation or have secured alternative places to go if they need to evacuate their homes may not use the nearest public shelter in a disaster. We recommend that policy makers consider the use of mechanical ventilation and the availability of non-public shelters as predictors of evacuation behavior when considering disaster preparedness for these patients.