ABSTRACT
In March of 2021, as the world marked the first anniversary since COVID-19 altered our reality, graduate social work students in Dr. Carol Tosone's Evidence-Based Trauma class at NYU considered the challenges of learning about trauma treatment while simultaneously living through a global trauma. Students reflected on their home lives, school experiences, field placements, mental health challenges, feelings of burnout, and the added complexities of racial disparities and injustices. Students also shared their coping mechanisms and hope for the future. This paper aims to provide insight into their varied experiences while relating their struggles and demonstrating their pathways toward resiliency.
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.