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Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease.
Jacobs J, Grum-Tokars V, Zhou Y, Turlington M, Saldanha SA, Chase P, Eggler A, Dawson ES, Baez-Santos YM, Tomar S, Mielech AM, Baker SC, Lindsley CW, Hodder P, Mesecar A, Stauffer SR
(2013) J Med Chem 56: 534-46
MeSH Terms: Acetamides, Drug Discovery, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Protease Inhibitors, SARS Virus, Severe Acute Respiratory Syndrome, Small Molecule Libraries, Structure-Activity Relationship
Show Abstract · Added March 7, 2014
A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.
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10 MeSH Terms
A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease.
Graham RL, Becker MM, Eckerle LD, Bolles M, Denison MR, Baric RS
(2012) Nat Med 18: 1820-6
MeSH Terms: Age Factors, Animals, Base Sequence, DNA Primers, Drug Design, Exoribonucleases, Female, Immunocompromised Host, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Plasmids, Real-Time Polymerase Chain Reaction, SARS Virus, Sequence Analysis, DNA, Severe Acute Respiratory Syndrome, Statistics, Nonparametric, Viral Vaccines, Virus Replication
Show Abstract · Added February 19, 2015
Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3'→5' exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses.
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19 MeSH Terms
Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing.
Eckerle LD, Becker MM, Halpin RA, Li K, Venter E, Lu X, Scherbakova S, Graham RL, Baric RS, Stockwell TB, Spiro DJ, Denison MR
(2010) PLoS Pathog 6: e1000896
MeSH Terms: Amino Acid Sequence, Animals, Chlorocebus aethiops, Evolution, Molecular, Exoribonucleases, Genetic Engineering, Genetic Variation, Genome, Viral, Models, Genetic, Molecular Sequence Data, Mutation, Phenotype, Polymorphism, Single Nucleotide, SARS Virus, Severe Acute Respiratory Syndrome, Vero Cells, Viral Nonstructural Proteins, Virus Replication
Show Abstract · Added August 16, 2012
Most RNA viruses lack the mechanisms to recognize and correct mutations that arise during genome replication, resulting in quasispecies diversity that is required for pathogenesis and adaptation. However, it is not known how viruses encoding large viral RNA genomes such as the Coronaviridae (26 to 32 kb) balance the requirements for genome stability and quasispecies diversity. Further, the limits of replication infidelity during replication of large RNA genomes and how decreased fidelity impacts virus fitness over time are not known. Our previous work demonstrated that genetic inactivation of the coronavirus exoribonuclease (ExoN) in nonstructural protein 14 (nsp14) of murine hepatitis virus results in a 15-fold decrease in replication fidelity. However, it is not known whether nsp14-ExoN is required for replication fidelity of all coronaviruses, nor the impact of decreased fidelity on genome diversity and fitness during replication and passage. We report here the engineering and recovery of nsp14-ExoN mutant viruses of severe acute respiratory syndrome coronavirus (SARS-CoV) that have stable growth defects and demonstrate a 21-fold increase in mutation frequency during replication in culture. Analysis of complete genome sequences from SARS-ExoN mutant viral clones revealed unique mutation sets in every genome examined from the same round of replication and a total of 100 unique mutations across the genome. Using novel bioinformatic tools and deep sequencing across the full-length genome following 10 population passages in vitro, we demonstrate retention of ExoN mutations and continued increased diversity and mutational load compared to wild-type SARS-CoV. The results define a novel genetic and bioinformatics model for introduction and identification of multi-allelic mutations in replication competent viruses that will be powerful tools for testing the effects of decreased fidelity and increased quasispecies diversity on viral replication, pathogenesis, and evolution.
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18 MeSH Terms
Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice.
Becker MM, Graham RL, Donaldson EF, Rockx B, Sims AC, Sheahan T, Pickles RJ, Corti D, Johnston RE, Baric RS, Denison MR
(2008) Proc Natl Acad Sci U S A 105: 19944-9
MeSH Terms: Amino Acid Sequence, Animals, Cells, Cultured, Chiroptera, Chlorocebus aethiops, Female, Humans, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Recombinant Proteins, Recombination, Genetic, Respiratory Mucosa, SARS Virus, Severe Acute Respiratory Syndrome, Spike Glycoprotein, Coronavirus, Vero Cells, Viral Envelope Proteins, Virus Replication, Zoonoses
Show Abstract · Added February 19, 2015
Defining prospective pathways by which zoonoses evolve and emerge as human pathogens is critical for anticipating and controlling both natural and deliberate pandemics. However, predicting tenable pathways of animal-to-human movement has been hindered by challenges in identifying reservoir species, cultivating zoonotic organisms in culture, and isolating full-length genomes for cloning and genetic studies. The ability to design and recover pathogens reconstituted from synthesized cDNAs has the potential to overcome these obstacles by allowing studies of replication and pathogenesis without identification of reservoir species or cultivation of primary isolates. Here, we report the design, synthesis, and recovery of the largest synthetic replicating life form, a 29.7-kb bat severe acute respiratory syndrome (SARS)-like coronavirus (Bat-SCoV), a likely progenitor to the SARS-CoV epidemic. To test a possible route of emergence from the noncultivable Bat-SCoV to human SARS-CoV, we designed a consensus Bat-SCoV genome and replaced the Bat-SCoV Spike receptor-binding domain (RBD) with the SARS-CoV RBD (Bat-SRBD). Bat-SRBD was infectious in cell culture and in mice and was efficiently neutralized by antibodies specific for both bat and human CoV Spike proteins. Rational design, synthesis, and recovery of hypothetical recombinant viruses can be used to investigate mechanisms of transspecies movement of zoonoses and has great potential to aid in rapid public health responses to known or predicted emerging microbial threats.
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21 MeSH Terms
One-year outcomes and health care utilization in survivors of severe acute respiratory syndrome.
Tansey CM, Louie M, Loeb M, Gold WL, Muller MP, de Jager J, Cameron JI, Tomlinson G, Mazzulli T, Walmsley SL, Rachlis AR, Mederski BD, Silverman M, Shainhouse Z, Ephtimios IE, Avendano M, Downey J, Styra R, Yamamura D, Gerson M, Stanbrook MB, Marras TK, Phillips EJ, Zamel N, Richardson SE, Slutsky AS, Herridge MS
(2007) Arch Intern Med 167: 1312-20
MeSH Terms: Adult, Delivery of Health Care, Disability Evaluation, Disease Outbreaks, Female, Follow-Up Studies, Humans, Male, Middle Aged, Ontario, Outcome Assessment, Health Care, Prognosis, Prospective Studies, Quality of Life, Respiratory Function Tests, Severe Acute Respiratory Syndrome, Surveys and Questionnaires, Walking
Show Abstract · Added March 30, 2020
BACKGROUND - Severe Acute Respiratory Syndrome (SARS) became a global epidemic in 2003. Comprehensive information on 1-year outcomes and health care utilization is lacking. Research conducted during the SARS outbreak may help inform research planning for future public health emergencies. The objective of this study was to evaluate the 1-year outcomes in survivors of SARS and their family caregivers.
METHOD - The study was prospective and observational. We evaluated 117 SARS survivors from Toronto, Ontario. Patients were interviewed and underwent physical examination, pulmonary function testing, chest radiography, a 6-minute-walk test, quality-of-life measures, and self-report of health care utilization. At 1 year, informal caregivers were identified for a survey on caregiver burden.
RESULTS - The enrolled survivors of SARS were young (median age, 42 years), and most were women (67%) and health care workers (65%). At 1 year after hospital discharge, pulmonary function measures were in the normal range, but 18% of patients had a significant reduction in distance walked in 6 minutes. The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) domains were 0.3 to 1.0 SD below normal at 1 year. Of the patients, 17% had not returned to work by 1 year. Fifty-one patients required 668 visits to psychiatry or psychology practitioners. During the SARS epidemic, informal caregivers reported a decline of 1.6 SD below normal on the mental component score of the SF-36.
CONCLUSIONS - Most SARS survivors had good physical recovery from their illness, but some patients and their caregivers reported a significant reduction in mental health 1 year later. Strategies to ameliorate the psychological burden of an epidemic on the patient and family caregiver should be considered as part of future pandemic planning.
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SARS coronavirus replicase proteins in pathogenesis.
Graham RL, Sparks JS, Eckerle LD, Sims AC, Denison MR
(2008) Virus Res 133: 88-100
MeSH Terms: Animals, Chlorocebus aethiops, Humans, Open Reading Frames, RNA-Dependent RNA Polymerase, SARS Virus, Severe Acute Respiratory Syndrome, Vero Cells, Viral Nonstructural Proteins, Virulence
Show Abstract · Added February 19, 2015
Much progress has been made in understanding the role of structural and accessory proteins in the pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) infections. The SARS epidemic also brought new attention to the proteins translated from ORF1a and ORF1b of the input genome RNA, also known as the replicase/transcriptase gene. Evidence for change within the ORF1ab coding sequence during the SARS epidemic, as well as evidence from studies with other coronaviruses, indicates that it is likely that the ORF1ab proteins play roles in virus pathogenesis distinct from or in addition to functions directly involved in viral replication. Recent reverse genetic studies have confirmed that proteins of ORF1ab may be involved in cellular signaling and modification of cellular gene expression, as well as virulence by mechanisms yet to be determined. Thus, the evolution of the ORF1ab proteins may be determined as much by issues of host range and virulence as they are by specific requirements for intracellular replication.
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10 MeSH Terms
Severe acute respiratory syndrome coronavirus pathogenesis, disease and vaccines: an update.
Denison MR
(2004) Pediatr Infect Dis J 23: S207-14
MeSH Terms: Adolescent, Adult, Age Factors, Animals, Antibodies, Viral, Child, Disease Models, Animal, Disease Outbreaks, Humans, SARS Virus, Severe Acute Respiratory Syndrome, Severity of Illness Index, Viral Vaccines, Zoonoses
Show Abstract · Added February 19, 2015
BACKGROUND - A novel coronavirus has recently been identified as the cause of severe acute respiratory syndrome (SARS-CoV). The ability of this family of positive strand RNA viruses to move between species and cause severe disease in humans, with the potential for pandemic spread, has been confirmed.
METHODS - An understanding of the disease and its pathogenesis and the genetics of coronavirus infections, as well as strategies to treat or prevent coronavirus infections, are essential. The history of coronavirus vaccines and the occurrence of laboratory-associated SARS-CoV infections underscore the need for stably attenuated strains of SARS-CoV and other coronaviruses.
RESULTS - Rapid progress has been made in understanding the clinical disease of SARS in adults and children. In adults, systemic infection with clinical and biochemical abnormalities, as well as respiratory infection, may be the rule. SARS is much milder in children younger than 12 years old than it is in adolescents and adults. In children age 12 years and younger, symptoms are generally nonspecific and cold-like. Numerous approaches to the development of SARS-CoV vaccines have been undertaken, and there is evidence that antibodies to the spike protein may be protective from replication and pathology in animal models.
CONCLUSIONS - The availability of reverse genetic systems has made it possible to engineer and recover coronavirus variants that contain multiple genetically stable mutations that grow well in culture but are attenuated for replication, virulence or both. Such variants will be platforms for the safe growth of SARS-CoV and candidates for live attenuated vaccines.
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Interpretation of diagnostic laboratory tests for severe acute respiratory syndrome: the Toronto experience.
Tang P, Louie M, Richardson SE, Smieja M, Simor AE, Jamieson F, Fearon M, Poutanen SM, Mazzulli T, Tellier R, Mahony J, Loeb M, Petrich A, Chernesky M, McGeer A, Low DE, Phillips E, Jones S, Bastien N, Li Y, Dick D, Grolla A, Fernando L, Booth TF, Henry B, Rachlis AR, Matukas LM, Rose DB, Lovinsky R, Walmsley S, Gold WL, Krajden S, Ontario Laboratory Working Group for the Rapid Diagnosis of Emerging Infections
(2004) CMAJ 170: 47-54
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Clinical Laboratory Techniques, Communicable Diseases, Emerging, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Ontario, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity, Severe Acute Respiratory Syndrome
Show Abstract · Added March 30, 2020
BACKGROUND - An outbreak of severe acute respiratory syndrome (SARS) began in Canada in February 2003. The initial diagnosis of SARS was based on clinical and epidemiological criteria. During the outbreak, molecular and serologic tests for the SARS-associated coronavirus (SARS-CoV) became available. However, without a "gold standard," it was impossible to determine the usefulness of these tests. We describe how these tests were used during the first phase of the SARS outbreak in Toronto and offer some recommendations that may be useful if SARS returns.
METHODS - We examined the results of all diagnostic laboratory tests used in 117 patients admitted to hospitals in Toronto who met the Health Canada criteria for suspect or probable SARS. Focusing on tests for SARS-CoV, we attempted to determine the optimal specimen types and timing of specimen collection.
RESULTS - Diagnostic test results for SARS-CoV were available for 110 of the 117 patients. SARS-CoV was detected by means of reverse-transcriptase polymerase chain reaction (RT-PCR) in at least one specimen in 59 (54.1%) of 109 patients. Serologic test results of convalescent samples were positive in 50 (96.2%) of 52 patients for whom paired serum samples were collected during the acute and convalescent phases of the illness. Of the 110 patients, 78 (70.9%) had specimens that tested positive by means of RT-PCR, serologic testing or both methods. The proportion of RT-PCR test results that were positive was similar between patients who met the criteria for suspect SARS (50.8%, 95% confidence interval [CI] 38.4%-63.2%) and those who met the criteria for probable SARS (58.0%, 95% CI 44.2%-70.7%). SARS-CoV was detected in nasopharyngeal swabs in 33 (32.4%) of 102 patients, in stool specimens in 19 (63.3%) of 30 patients, and in specimens from the lower respiratory tract in 10 (58.8%) of 17 patients.
INTERPRETATION - These findings suggest that the rapid diagnostic tests in use at the time of the initial outbreak lack sufficient sensitivity to be used clinically to rule out SARS. As tests for SARS-CoV continue to be optimized, evaluation of the clinical presentation and elucidation of a contact history must remain the cornerstone of SARS diagnosis. In patients with SARS, specimens taken from the lower respiratory tract and stool samples test positive by means of RT-PCR more often than do samples taken from other areas.
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Reverse genetics with a full-length infectious cDNA of severe acute respiratory syndrome coronavirus.
Yount B, Curtis KM, Fritz EA, Hensley LE, Jahrling PB, Prentice E, Denison MR, Geisbert TW, Baric RS
(2003) Proc Natl Acad Sci U S A 100: 12995-3000
MeSH Terms: Animals, Base Sequence, Chlorocebus aethiops, Cloning, Molecular, Consensus Sequence, DNA, Complementary, Genetic Markers, Genetic Techniques, Humans, Open Reading Frames, SARS Virus, Severe Acute Respiratory Syndrome, Transcription, Genetic, Vero Cells
Show Abstract · Added February 19, 2015
A previously undescribed coronavirus (CoV) is the etiologic agent responsible for severe acute respiratory syndrome (SARS). Using a panel of contiguous cDNAs that span the entire genome, we have assembled a full-length cDNA of the SARS-CoV Urbani strain, and have rescued molecularly cloned SARS viruses (infectious clone SARS-CoV) that contained the expected marker mutations inserted into the component clones. Recombinant viruses replicated as efficiently as WT virus and both were inhibited by treatment with the cysteine proteinase inhibitor (2S,3S)-transepoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester. In addition, subgenomic transcripts were initiated from the consensus sequence ACGAAC in both the WT and infectious clone SARS-CoV. Availability of a SARS-CoV full-length cDNA provides a template for manipulation of the viral genome, allowing for the rapid and rational development and testing of candidate vaccines and therapeutics against this important human pathogen.
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Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada.
Knowles SR, Phillips EJ, Dresser L, Matukas L
(2003) Clin Infect Dis 37: 1139-42
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Anemia, Hemolytic, Antiviral Agents, Canada, Disease Outbreaks, Female, Humans, Hypocalcemia, Male, Middle Aged, Ribavirin, Severe Acute Respiratory Syndrome
Show Abstract · Added March 30, 2020
Although information on efficacy and adverse drug reactions is lacking, ribavirin has been used empirically for the treatment of severe acute respiratory syndrome (SARS). We report common adverse events in 110 patients with suspected or probable SARS who were treated with ribavirin. Sixty-one percent of the patients had evidence of hemolytic anemia, and hypocalcemia and hypomagnesmia were reported in 58% and 46% of patients, respectively.
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