Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we design a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibits PLpro with kinact/KI = 9,600 M−1 s−1, achieves sub-μM EC50 values against three SARS-CoV-2 variants in mammalian cell lines, and does not inhibit a panel of human deubiquitinases (DUBs) at >30 μM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validates our design strategy and establishes the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.
Fear avoidance model of chronic pain-based interventions are effective, but have not been successfully implemented into primary care. It was hypothesized that speed walking times and key measures of the fear avoidance model would improve following the brief intervention delivered in primary care. A brief primary care-based intervention (PCB) that included a single educational session, speed walking (an in vivo desensitization exposure task), and visual performance feedback was designed to reduce fear avoidance beliefs and improve function in 4 patients with chronic low back pain. A multiple baseline across subjects with a changing criterion design indicated that speed walking times improved from baseline only after the PCB intervention was delivered. Six fear avoidance model outcome measures improved from baseline to end of study and five of six outcome measures improved from end of study to follow-up. This study provides evidence for the efficacy of a brief PCB fear avoidance intervention that was successfully implemented into a busy clinic for the treatment of chronic pain.
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