A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019–2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1–4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds—including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds—as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our 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. A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.

/pdf/structure-of-mpro-from-sars-cov-2-and-discovery-of-its-2hyiph66s6.pdf

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by coronaviruses, have attracted substantial attention owing to their high mortality rates and potential to cause epidemics. Yuen and colleagues discuss progress with treatment options for these syndromes, including virus- and host-targeted drugs, and the challenges that need to be overcome in their further development. In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.

/pdf/coronaviruses-drug-discovery-and-therapeutic-options-1rkhv204qf.pdf

Coronaviruses - drug discovery and therapeutic options.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.

SUMMARY The source of the severe acute respiratory syndrome (SARS) epidemic was traced to wildlife market civets and ultimately to bats. Subsequent hunting for novel coronaviruses (CoVs) led to the discovery of two additional human and over 40 animal CoVs, including the prototype lineage C betacoronaviruses, Tylonycteris bat CoV HKU4 and Pipistrellus bat CoV HKU5; these are phylogenetically closely related to the Middle East respiratory syndrome (MERS) CoV, which has affected more than 1,000 patients with over 35% fatality since its emergence in 2012. All primary cases of MERS are epidemiologically linked to the Middle East. Some of these patients had contacted camels which shed virus and/or had positive serology. Most secondary cases are related to health care-associated clusters. The disease is especially severe in elderly men with comorbidities. Clinical severity may be related to MERS-CoV9s ability to infect a broad range of cells with DPP4 expression, evade the host innate immune response, and induce cytokine dysregulation. Reverse transcription-PCR on respiratory and/or extrapulmonary specimens rapidly establishes diagnosis. Supportive treatment with extracorporeal membrane oxygenation and dialysis is often required in patients with organ failure. Antivirals with potent in vitro activities include neutralizing monoclonal antibodies, antiviral peptides, interferons, mycophenolic acid, and lopinavir. They should be evaluated in suitable animal models before clinical trials. Developing an effective camel MERS-CoV vaccine and implementing appropriate infection control measures may control the continuing epidemic.

/pdf/middle-east-respiratory-syndrome-coronavirus-another-3rpyownr3e.pdf

Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease

There were severe panics caused by Severe Acute Respiratory Syndrome (SARS) and Middle-East Respiratory Syndrome-Coronavirus. Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, we applied a flavonoid library to systematically probe inhibitory compounds against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymatic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking analysis indicated that S1, S2 and S3' sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a critical role in objecting false positive or overestimated inhibitory activity of flavonoids. With the systematic analysis, the three flavonoids are suggested to be templates to design functionally improved inhibitors.

Inhibition of SARS-CoV 3CL protease by flavonoids.

Emerging Infection Disease Program, High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biomedicine and Technology, Tianjin 300457, China Correspondence: raozh@xtal.tsinghua.edu.cnFrom the global outbreak of SARS-CoV caused infection disease in 2003, coronaviruses (CoVs) are known to be a great threat to the human health. Recently, a new SARS-like coronavirus, human betacoronavirus 2c EMC/2012 (HCoV-EMC), has been identified and the appearance of this new CoV raises concerns that a new spread of CoV may occurs in the future. By solving the crystal structure of HCoV-EMC main protease with a wide-spectrum anti-CoV inhibitor N3, we conﬁ rmed that that N3 blocks the function of HCoV-EMC main protease through a similar mechanism to other CoVs. Together with the good pharmaceutical features, N3 is conceiv-able to be effective to HCoV-EMC and other CoVs appearing in the future. These ﬁ ndings make it convincing that CoVs will not be a threat to human health.In the year of 2012, a new respira-tory illness similar to severe acute res-piratory syndrome (SARS) that spread globally in 2003 and infected over 8,000 people with more than 800 fatalities (Li et al., 2010), was identiﬁ ed in Europe, the Middle East and Hong Kong. The infection was reported to manifest clini-cally with fever, cough and breathing dif-ﬁ culties. Some patients also developed acute renal failure. Sequence analysis suggested that the causative agent of this newly emerged SARS-like illness is a new coronavirus (CoV) which has been named as the human betacorona-virus 2c EMC/2012 (HCoV-EMC). No clinically approved treatment is available for CoV infection since the outbreak of SARS in 2003, the appearance of this new CoV raises concerns that a new epidemic of CoV infection may occur in future.CoVs are positive-sense, single-stranded RNA viruses and are featured by the largest viral RNA genomes known to date (Yang et al., 2003). Rep-lication of coronavirus requires correct proteolytic processing of the replicase polyprotein by viral proteases, in particu-lar a chymotrypsin-like protease (3CL

/pdf/the-newly-emerged-sars-like-coronavirus-hcov-emc-also-has-an-21cphmvpbs.pdf

The newly emerged SARS-Like coronavirus HCoV-EMC also has an 'Achilles' heel': current effective inhibitor targeting a 3C-like protease

The invention provides application of isatin thiosemicarbazone compound with the following general formula (I) in preparing medicament for inhibiting activity of NDM-1. In the formula (I), R1 is selected from the group consisting of hydrogen and C5-C10 aralkyl; R2 is selected from the group consisting of hydrogen, C1-C4 alkyl and halogen; and R3 is selected from the group consisting of hydrogen and C1-C4 alkyl. The compound can significantly inhibit the activity of NDM-1.

Application of isatin thiosemicarbazone compound in inhibition of NDM-1 activity

The invention relates to a crystal structure of beta-lactamase NDM-1. The beta-lactamase NDM-1 is a coding gene of approximately 40-50 site to approximately 260-270 site amino acids of a beta-lactamase NDM-1 full-length protein sequence. Atoms in a crystal three-dimensional structure have at least 40% of atomic coordinates listed in the table 1, or an average root variance between main-chain carbon skeleton atomic-structure coordinates of at least 40% amino acids in the beta-lactamase NDM-1 crystal three-dimensional structure and coordinates in the table 1 is smaller than or equal to 1.5 angstrom. The invention also relates to a method for purifying beta-lactamase NDM-1, and an application of the beta-lactamase NDM-1 crystal three-dimensional structure in medicine screening and medicine designing.

Expression and purification of super-bacteria New-Delhi-Metallo-dependent beta-lactamase NDM-1, and crystal structure of beta-lactamase NDM-1

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The newly emerged SARS-Like coronavirus HCoV-EMC also has an 'Achilles' heel': current effective inhibitor targeting a 3C-like protease

Application of isatin thiosemicarbazone compound in inhibition of NDM-1 activity

Expression and purification of super-bacteria New-Delhi-Metallo-dependent beta-lactamase NDM-1, and crystal structure of beta-lactamase NDM-1