RESUMO
The COVID-19 pandemic is a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Future pandemics could be prevented by accessible, easily deployable broad-spectrum oral antivirals and open knowledge bases that derisk and accelerate novel antiviral discovery and development. Here, we report the results of the COVID Moonshot, a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical scaffold that is differentiated from current clinical candidates in terms of toxicity, resistance, and pharmacokinetics liabilities, and developed it into noncovalent orally-bioavailable nanomolar inhibitors with clinical potential. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations. In the process, we generated a detailed map of the structural plasticity of the main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>500 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.
RESUMO
Unique insights of key delivery staff and successful delivery strategies used to overcome cultural barriers were obtained through intensive interviews with fifty staff members. Participants in the study were identified as knowledgeable staff members by project coordinators. An open-ended qualitative methodology was used to interview staff members about barriers they faced in delivering services to new populations and strategies that were used to address these barriers. Fifty interviews were completed. Of those, forty-two interviewees were frontline staff members and eight were "hands-on" administrators. Fifteen of these staff members worked in programs that were targeted to urban dwelling Latino families and ten served urban African-Americans. Of the twenty-five staff members who worked in programs targeted to rural populations, eight worked to provide respite to African-American families while four served rural Latinos. The remaining thirteen interviewees served rural families of all ethnic groups. Interviews were tape recorded for accuracy and later transcribed. Emergent themes include: successful vs. unsuccessful service efforts, diversity of caregivers within ethnic groups, staff members' perceptions of their clients, staffing patterns, cultural views of Alzheimer's disease, service use in general, and government assistance. Concrete examples from staff members' experiences are used to illustrate these themes.
