ABSTRACT
Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.
Subject(s)
Adenoviridae/drug effects , Antiviral Agents/pharmacology , Coronavirus/drug effects , HIV-1/drug effects , RNA Processing, Post-Transcriptional/drug effects , Thiazoles/pharmacology , Virus Replication/drug effects , Adenoviridae/physiology , Antiviral Agents/chemistry , Cell Line , Coronavirus/classification , Coronavirus/physiology , Gene Expression/drug effects , HIV-1/physiology , Humans , RNA Splicing Factors/metabolism , RNA, Viral/metabolism , Thiazoles/chemistryABSTRACT
Given the collective trauma caused by COVID-19 global pandemic, it is more important than ever that schools look for ways to create safe, trauma-sensitive, and restorative learning environments. This article presents implementation science, readiness assessments, and ongoing evaluation as central and integral to all efforts that seek to transform punitive schools into restorative schools. The author first presents five elements of a school’s relational ecology as a framework for comparing a punitive school to a restorative school: structure, leadership, staff, students, and response to behavioral incidents. Then, the author calls upon school administrators, as well as restorative justice trainers who work with schools, to utilize a systems change approach that supports whole-school change. Without a full commitment to systems change, restorative justice in education (RJE) will continue to fall short of expectations and the educational system itself will continue to cause the same harm to marginalized students as it did prior to the pandemic.