The COVID-19 pandemic caused by SARS-CoV-2 is a health threat worldwide. Viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is potent inhibitor for the Mpro encoded by SARS-CoV-2 with half-maximum inhibitory concentration (IC50) of 26.4±1.1 nM. In this study, we also show that GC376 inhibits SARS-CoV-2 replication with a half-maximum effective concentration (EC50) of 0.91±0.03 μM. Only a small portion of SARS-CoV-2-Mpro was covalently modified in the excess of GC376 as evaluated by mass spectrometry analysis; indicating that improved inhibitors are needed. Subsequently, molecular docking analysis revealing the recognition and binding groups of GC376 within the active site of SARS-CoV-2 Mpro provides important new information for the optimization of GC376. Given that sufficient safety and efficacy data are available for GC376 as an investigational veterinary drug, expedited development of GC376, or its optimized analogues, for treatment of SARS-CoV-2 infection in human is recommended.
We discovered that neuropilin 1 (NRP1) is a new receptor candidate to mediate Enterovirus A71 (EVA71) into cells. In the engineered form as a decoy receptor, NRP1 was able to recognize and neutralize EVA71 but not EV-D68 and CVB3. NRP1 recognizes EVA71 through a novel domain on VP3 capsid protein. The principle in the design, engineering and refinement of the NRP1-based decoy receptor described in this study represents a general and well-suited antiviral strategy.
Longitudinal epidemiological studies are considered the gold standard for understanding craniofacial morphologic development, but participant recruitment and retention can be challenging. This study describes strategies used to recruit and maintain a high level of participation in a longitudinal study involving annual three-dimensional (3D) craniofacial soft-tissue imaging from healthy Taiwanese Chinese elementary school students aged 6 to 12 years. The key aspects for project delineation, implementation, and the initial three-year practical experiment are portrayed in an integrated multistep workflow: ethics- and grant-related issues; contact, approval, and engagement from partners of the project (school stakeholders and parents); a didactic approach to recruit the students; research staff composition with task design; three station-based data collection days with two educative activities (oral hygiene and psychosocial interaction stations) and one 3D craniofacial imaging activity; and reinforcement tactics to sustain the longitudinal annual participation after the first enrollment. Randomly selected students and teachers answered an experience satisfaction questionnaire (five-point Likert scale ranging from one to five) designed to assist in understanding what they think about the data collection day. Measures of frequency (percentage) and central tendency (mean) were adopted for descriptive analysis. Six of seven contacted schools accepted participation in the project. All parents who attended the explanatory meetings agreed to join the project. A cohort of 676 students (336 girls) participated at baseline enrollment, with a follow-up rate of 96% in the second data collection. The average questionnaire-related scores were 4.2 ± 0.7 and 4.4 ± 0.6 for teachers and students, respectively. These 3D craniofacial norms will benefit multidisciplinary teams managing cleft-craniofacial deformities in the globally distributed ethnic Chinese population, particularly useful for phenotypic variation characterization, conducting quantitative morphologic comparisons, and therapeutic planning and outcome assessment. The described pathway model will assist other groups to establish their own age-, sex-, and ethnic-specific normative databases.
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