The COVID-19 (Coronavirus disease-2019) pandemic, caused by the SARS-CoV-2 coronavirus, is a significant threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and MERS-CoV. Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analysis for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 Orf9b, an interaction we structurally characterized using cryo-EM. Combining genetically-validated host factors with both COVID-19 patient genetic data and medical billing records identified important molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented.

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To establish the activity of sigma ligands at sigma1 and sigma2 receptor, we chose two tumour cell lines, the human SK-N-SH neuroblastoma and the rat C6 glioma lines, which express sigma2 receptors at a high density and sigma1 receptors in their high-affinity or low-affinity state. We tested the sigma2 receptor agonist PB28 and the sigma2 antagonist AC927, and (+)-pentazocine and NE100 as agonist and antagonist, respectively, at sigma1 receptors, with regard to antiproliferative and cytotoxic effects. In addition, 1,3-di(2-tolyl)guanidine (DTG) and haloperidol were tested as reference compounds displaying nearly equipotent sigma affinity (sigma2>sigma1 and sigma1>sigma2, respectively). In both SK-N-SH and C6 cells, PB28 and NE100 displayed the most potent results both in antiproliferative and cytotoxic assay while AC927 and (+)-pentazocine were inactive in both assays. The cytotoxic and antiproliferative effects of DTG and haloperidol reflected their sigma1 antagonist activity and sigma2 agonist activity. Moreover, our results in the tumour cell lines correlated well with those for sigma2 activity found previously in a functional assay in the guinea-pig bladder. These findings establish a new model for evaluating both sigma2 and sigma1 receptor activity of sigma ligands, which could be useful for developing new ligands having mixed sigma2 agonist/sigma1 antagonist activity as potential antineoplastic agents.

S Ligands have recently been shown to have cytotoxic activity, to induce ceramide-dependent/caspase-independent apoptosis, and to down-regulate P-glycoprotein (P-gp) mRNA levels in some mouse and human models. In this study, we verified whether a mixed S 2 agonist/S 1 antagonist, PB28, was able to have antitumor activity and to enhance anthracycline efficacy in two human breast cancer cell lines, MCF7 and MCF7 ADR, both characterized by significant S 2 receptor expression, by high and low S 1 receptor expression, and low and high P-gp expression, respectively. In both cell lines, PB28 showed high S 2 receptor affinity and low S 1 receptor affinity; furthermore, it inhibited cell growth with a clear effect at 48 hours (IC 50 in nanomolar range), a consistent time exposure-independent increase of G 0 -G 1 -phase fraction (of f20% of both cell lines) and caspase-independent apoptosis (15% increased after 1-day drug exposure). PB28 also reduced P-gp expression in a concentration-and time-dependent manner (f60% in MCF7 and 90% in MCF7 ADR). We showed also a strong synergism between PB28 and doxorubicin by adopting either simultaneous or sequential schedules of the two drugs. We suggest that this synergism could depend on PB28-induced increase of intracellular accumulation of doxorubicin (f50% in MCF7 and 75% in MCF7 ADR by flow cytometry analysis). In conclusion, we suggest that the S 2 agonist PB28 could be an interesting antitumor agent either in monotherapy or in combination with conventional drugs.