A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan [1][2][3][4] . Currently there are no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (M pro ). M pro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus 5,6 . Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus M pro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of M pro . Six of these compounds inhibited M pro with IC 50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.CoVs infect humans and other animal species, causing a variety of highly prevalent and severe diseases, including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) 7 . The COVID-19 virus genome is comprised of ~30,000 nucleotides; its replicase gene encodes two overlapping polyproteins, pp1a and pp1ab, required for viral replication and transcription 3,4 . The functional polypeptides are released from the polyproteins by extensive proteolytic processing, predominantly by a 33.8-kDa main protease (M pro ), also referred to as the 3C-like protease. M pro digests the polyprotein at no less than 11 conserved sites, starting with the autolytic cleavage of this enzyme itself from pp1a and pp1ab 8 . The functional importance of M pro in the viral life cycle, together with the absence of closely related homologues in humans, identify the M pro as an attractive target for antiviral drug design 9 .To facilitate the rapid discovery of antiviral compounds with clinical potential, we developed a strategy combining structure-assisted drug design, virtual drug screening and high-throughput screening to repurpose existing drugs to target COVID-19 virus M pro . Establishing a high-throughput activity assayRecombinant COVID-19 virus M pro with native N and C termini was expressed in Escherichia coli and subsequently purified (Extended Data Fig. 1a, b). The molecular weight of COVID-19 virus M pro as determined by mass spectroscopy is 33797.0 Da, consistent with its theoretical molecular weight 337...

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circMTO1 suppresses HCC progression by acting as the sponge of oncogenic miR-9 to promote p21 expression, suggesting that circMTO1 is a potential target in HCC treatment. The decrease of circMTO1 in HCC tissues may serve as a prognosis predictor for poor survival of patients. (Hepatology 2017;66:1151-1164).

Evidence accumulated over more than 45 years has indicated that environmental stimuli can induce craving for drugs of abuse in individuals who have addictive disorders. However, the brain mechanisms that subserve such craving have not been elucidated. Here a positron emission tomographic study shows increased glucose metabolism in cortical and limbic regions implicated in several forms of memory when human volunteers who abuse cocaine are exposed to drug-related stimuli. Correlations of metabolic increases in the dorsolateral prefrontal cortex, medial temporal lobe (amygdala), and cerebellum with self-reports of craving suggest that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving.Most individuals who suffer from dependence on cocaine and other addictive drugs return to substance abuse within a year of initiating abstinence (1, 2). Addicts often attribute relapse to intense desire or "craving," which may arise in an environment associated with drug use (3-5). Moreover, drug-related cues can induce craving in laboratory settings (6-8). Substantial interest focuses on the mechanisms by which drug-related stimuli elicit craving (3, 5, 9-12) despite concerns that craving does not inevitably lead to drug taking (13). Little is known, however, about the biological basis of cue-elicited drug craving, except that cocaine users exposed to drug-related cues exhibit diffuse decreases in the power of the electroencephalogram (8). The purpose of the present study was to identify brain regions that mediate cue-elicited cocaine craving. To this end, regional cerebral metabolic rate for glucose (rCMRglc), an index of local brain function (14, 15), was measured in cocaine abusers and normal volunteers in a neutral test session and in another session during which cocaine-related stimuli were presented. METHODS Subjects. Thirteen cocaine abusers (COC group; 25-42 years old; 12 men, 1 woman; 12 Black, 1 White) and 5 normal volunteers (24-29 years old; 4 men, 1 woman; all Black) participated in the study. Evidence of physical disease, history of head trauma with loss of consciousness, or fulfillment of criteria for any axis I psychiatric diagnosis other than substance abuse or dependence or for any axis II disorder other than borderline or antisocial personality disorder were exclusionary criteria (16). Subjects in the COC group reported long-term cocaine use (median 8 years; range 2.5-20 years) with a current median use of 2.5 g/week (range 0.2-4.3 g/week). They also reported using opiates (5/13 subjects), marijuana (9/13), alcohol (13/13), and nicotine (11/13), but were not physically dependent on opiates or alcohol, nor were any of them receiving treatment for drug abuse. Some control subjects used nicotine (3/5), and alcohol (3/5); one reported a single use of marijuana more than a decade before the study. All volunteers in both groups had been abstinent from nicotine, alcohol, and caffeine for 12-15 h prior to each test session. Eight...