Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL pro ). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CL pro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CL pro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

This report describes the stereoselective synthesis of 3-azido-tetralins, -chromanes, and -tetrahydroquinolines via a tandem allylic azide rearrangement/Friedel-Crafts alkylation. Exposure of allylic azides with a pendant trichloroacetimidate to catalytic quantities of AgSbF proved optimal for this transformation. This cascade successfully differentiates the equilibrating azide isomers, providing products in excellent yield and selectivity (>25 examples, up to 94% yield and >25:1 dr). In many cases, the reactive isomer is only a trace fraction of the equilibrium mixture, keenly illustrating the dynamic nature of these systems. We demonstrate the utility of this process via a synthesis of hasubanan.

Epithelial barrier dysfunction during human immunodeficiency virus (HIV) infection has largely been attributed to the rapid and severe depletion of CD4؉ T cells in the gastrointestinal (GI) tract. Although it is known that changes in mucosal gene expression contribute to intestinal enteropathy, the role of small noncoding RNAs, specifically microRNA (miRNA), has not been investigated. Using the simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV pathogenesis, we investigated the effect of viral infection on miRNA expression in intestinal mucosa. SIV infection led to a striking decrease in the expression of mucosal miRNA compared to that in uninfected controls. This decrease coincided with an increase in 5=-3=-exoribonuclease 2 protein and alterations in DICER1 and Argonaute 2 expression. Targets of depleted miRNA belonged to molecular pathways involved in epithelial proliferation, differentiation, and immune response. Decreased expression of several miRNA involved in maintaining epithelial homeostasis in the gut was localized to the proliferative crypt region of the intestinal epithelium. Our findings suggest that SIV-induced decreased expression of miRNA involved in epithelial homeostasis, disrupted expression of miRNA biogenesis machinery, and increased expression of XRN2 are involved in the development of epithelial barrier dysfunction and gastroenteropathy. IMPORTANCEMicroRNA (miRNA) regulate the development and function of intestinal epithelial cells, and many viruses disrupt normal host miRNA expression. In this study, we demonstrate that SIV and HIV disrupt expression of miRNA in the small intestine during infection. The depletion of several key miRNA is localized to the proliferative crypt region of the gut epithelium. These miRNA are known to control expression of genes involved in inflammation, cell death, and epithelial maturation. Our data indicate that this disruption might be caused by altered expression of miRNA biogenesis machinery during infection. These findings suggest that the disruption of miRNA in the small intestine likely plays a role in intestinal enteropathy during HIV infection.

The phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affinity. Selective ligands for the 5-HT 2B , 5-HT 7 , and σ 1 receptors were identified, each with low nanomolar binding affinities. The σ 1 receptor affinity was supported in a cellular assay that provided evidence for increased cell survival under oxidative stress. KEYWORDS: 5-HT 7 , serotonin receptors, σ receptor, σ 1 receptor, G protein-coupled receptors, neuroprotection G protein-coupled receptors (GPCRs) are a prominent pharmacological target. More than 30% of FDA approved drugs target at least one GPCR. 1,2 Worldwide, more than 25% of drug sales come from GPCR modulating compounds. 3 GPCR modulators are used to treat a wide variety of diseases and disorders including allergies, 4 schizophrenia, 5 depression, 6 pain management, 7 and asthma. 8 Common GPCR targeting pharmaceuticals 9 include the antihistamine loratadine, 4 antidepressants fluoxetine and sertraline, 6 antipsychotics aripiprazole, clozapine, and haloperidol, 5 the opioids morphine, hydrocodone, and fentanyl, 7 and bronchodilators salbutamol and tiotropium bromide. 10 The phenethylamine core is a privileged substructure in GPCR ligands (Figure 1). This is partially because several endogenous neurotransmitters or neuromodulators are phenethylamines including dopamine 11 and epinephrine 12 (Figure 1a). The phenethylamine backbone is also found in a wide variety of GPCR targeting active pharmaceutical ingredients including morphine, salbutamol, and pseudoephedrine (Figure 1b).We recently developed a tandem Winstein rearrangement Friedel−Crafts alkylation that enabled the synthesis of differentially functionalized heterocyclic tertiary azides from

Collaboration among scientists has a major influence on scientific progress. Such collaboration often results from scientific meetings, where scientists gather to present and discuss their research and to meet potential collaborators. However, most scientific meetings have inherent biases, such as the availability of research funding or the selection bias of professional societies that make it difficult to study the effect of the meeting per se on scientific productivity. To evaluate the effects of scientific meetings on collaboration and progress independent of these biases, we conducted a study of the annual symposia held by the International Milk Genomics Consortium (IMGC) over a 12-year period. In our study, we conducted permutation testing to analyze the effectiveness of the IMGC in facilitating collaboration and productivity in a community of milk scientists who were meeting attendees relative to non-attendees. Using the number of co-authorships on published papers as a measure of collaboration, our analysis revealed that scientists who attended the symposium were associated with more collaboration than were scientists who did not attend. Furthermore, we evaluated the scientific progress of consortium attendees by analyzing publication rate and article impact. We found that IMGC attendees, in addition to being more collaborative, were also more productive and influential than were non-attendees who published in the same field. The results of our study suggest that the annual symposium encouraged interactions among disparate scientists and increased research productivity, exemplifying the positive effect of scientific meetings on both collaboration and progress.