The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

Cell signalling and endocytic membrane trafficking have traditionally been viewed as distinct processes. Although our present understanding is incomplete and there are still great controversies, it is now recognized that these processes are intimately and bidirectionally linked in animal cells. Indeed, many recent examples illustrate how endocytosis regulates receptor signalling (including signalling from receptor tyrosine kinases and G protein-coupled receptors) and, conversely, how signalling regulates the endocytic pathway. The mechanistic and functional principles that underlie the relationship between signalling and endocytosis in cell biology are becoming increasingly evident across many systems.Cells sense the environment and communicate with each other through the ligand-induced activation of signalling receptors at the cell surface. Signalling receptors, similar to other integral plasma membrane proteins, enter the endocytic pathway and are sorted into various endosomal compartments. Endocytosis regulates cell signalling most simply by controlling the number of receptors available for activation in the plasma membrane, and the activation of receptors or downstream effectors often stimulates receptor endocytosis. Studies of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) have established many examples of this relationship, which functions as a homeostatic regulatory loop to prevent excessive ligand-induced activation of downstream effectors. This paradigm has also been expanded to other receptors, including those for transforming growth factor-β (TGFβ), cytokines, Wnt and Notch. Furthermore, a functionally important relationship between signalling and endocytosis has been convincingly established in worm, fly, zebrafish, frog and mouse models.It is increasingly clear that endocytosis has many effects on signal transduction and, conversely, that receptor signalling regulates the endocytic machinery. This has blurred traditional lines that separate signalling and endocytosis at both the mechanistic and functional levels. Several cellular proteins that function in signalling and endocytosis have also been identified. This limits the degree to which signalling and endocytic machineries can be independently manipulated experimentally, which makes it challenging to precisely elucidate specific relationships between these machineries. There is now a vast collection of published primary literature on this topic, and numerous recent reviews have focused on its various aspects 1,2 . Instead, in this Review we discuss a limited subset of studies that illustrate the major features of the signalling-endocytosis nexus and represent the field more generally. We also attempt

The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the ␤ 2 -adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts. Receptor Pharmacology for the New MillenniumFor the last half-century, pharmacological theory has posited that ligands could be characterized by the nature of the functional effects elicited by their interaction with their tar-