A Versatile Strategy for Screening Custom-Designed Warhead-Armed Cyclic Peptide Inhibitors.

Demand for peptide-based pharmaceuticals has been steadily increasing, but only limited success has been achieved to date. To expedite peptide-based drug discovery, we developed a general scheme for cell-based screening of cyclic peptide inhibitors armed with a user-designed warhead. We combined unnatural amino acid incorporation and split intein-mediated peptide cyclization techniques and integrated a yeast-based colorimetric screening assay to generate a new scheme that we call the custom-designed warhead-armed cyclic peptide screening platform (CWCPS). This strategy successfully discovered a potent inhibitor, CY5-6Q, that targets human histone deacetylase 8 (HDAC8) with a KD value of 15 nM. This approach can be a versatile and general platform for discovering cyclic peptide inhibitors.

tRNA engineering strategies for genetic code expansion.

The advancement of genetic code expansion (GCE) technology is attributed to the establishment of specific aminoacyl-tRNA synthetase/tRNA pairs. While earlier improvements mainly focused on aminoacyl-tRNA synthetases, recent studies have highlighted the importance of optimizing tRNA sequences to enhance both unnatural amino acid incorporation efficiency and orthogonality. Given the crucial role of tRNAs in the translation process and their substantial impact on overall GCE efficiency, ongoing efforts are dedicated to the development of tRNA engineering techniques. This review explores diverse tRNA engineering approaches and provides illustrative examples in the context of GCE, offering insights into the user-friendly implementation of GCE technology.

Acceptability of a Health Care App With 3 User Interfaces for Older Adults and Their Caregivers: Design and Evaluation Study.

BACKGROUND: The older population needs solutions for independent living and reducing the burden on caregivers while maintaining the quality and dignity of life. OBJECTIVE: The aim of this study was to design, develop, and evaluate an older adult health care app that supports trained caregivers (ie, formal caregivers) and relatives (ie, informal caregivers). We aimed to identify the factors that affect user acceptance of interfaces depending on the user's role. METHODS: We designed and developed an app with 3 user interfaces that enable remote sensing of an older adult's daily activities and behaviors. We conducted user evaluations (N=25) with older adults and their formal and informal caregivers to obtain an overall impression of the health care monitoring app in terms of user experience and usability. In our design study, the participants had firsthand experience with our app, followed by a questionnaire and individual interview to express their opinions on the app. Through the interview, we also identified their views on each user interface and interaction modality to identify the relationship between the user's role and their acceptance of a particular interface. The questionnaire answers were statistically analyzed, and we coded the interview answers based on keywords related to a participant's experience, for example, ease of use and usefulness. RESULTS: We obtained overall positive results in the user evaluation of our app regarding key aspects such as efficiency, perspicuity, dependability, stimulation, and novelty, with an average between 1.74 (SD 1.02) and 2.18 (SD 0.93) on a scale of -3.0 to 3.0. The overall impression of our app was favorable, and we identified that "simple" and "intuitive" were the main factors affecting older adults' and caregivers' preference for the user interface and interaction modality. We also identified a positive user acceptance of the use of augmented reality by 91% (10/11) of the older adults to share information with their formal and informal caregivers. CONCLUSIONS: To address the need for a study to evaluate the user experience and user acceptance by older adults as well as both formal and informal caregivers regarding the user interfaces with multimodal interaction in the context of health monitoring, we designed, developed, and conducted user evaluations with the target user groups. Our results through this design study show important implications for designing future health monitoring apps with multiple interaction modalities and intuitive user interfaces in the older adult health care domain.

Bioorthogonal CRISPR/Cas9-Drug Conjugate: A Combinatorial Nanomedicine Platform.

Bioconjugation of proteins can substantially expand the opportunities in biopharmaceutical development, however, applications are limited for the gene editing machinery despite its tremendous therapeutic potential. Here, a self-delivered nanomedicine platform based on bioorthogonal CRISPR/Cas9 conjugates, which can be armed with a chemotherapeutic drug for combinatorial therapy is introduced. It is demonstrated that multi-functionalized Cas9 with a drug and polymer can form self-condensed nanocomplexes, and induce significant gene editing upon delivery while avoiding the use of a conventional carrier formulation. It is shown that the nanomedicine platform can be applied for combinatorial therapy by incorporating the anti-cancer drug olaparib and targeting the RAD52 gene, leading to significant anti-tumor effects in BRCA-mutant cancer. The current development provides a versatile nanomedicine platform for combination treatment of human diseases such as cancer.