PMC:7571312 / 8398-10191 JSON TXT

Annnotations TAB JSON ListView MergeView

LitCovid-PD-MONDO

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T41","span":{"begin":44,"end":48},"obj":"Disease"},{"id":"T42","span":{"begin":745,"end":749},"obj":"Disease"},{"id":"T43","span":{"begin":846,"end":850},"obj":"Disease"},{"id":"T44","span":{"begin":993,"end":1001},"obj":"Disease"},{"id":"T45","span":{"begin":1073,"end":1077},"obj":"Disease"},{"id":"T46","span":{"begin":1447,"end":1455},"obj":"Disease"},{"id":"T47","span":{"begin":1563,"end":1567},"obj":"Disease"},{"id":"T48","span":{"begin":1784,"end":1792},"obj":"Disease"}],"attributes":[{"id":"A41","pred":"mondo_id","subj":"T41","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A42","pred":"mondo_id","subj":"T42","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A43","pred":"mondo_id","subj":"T43","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A44","pred":"mondo_id","subj":"T44","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A45","pred":"mondo_id","subj":"T45","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A46","pred":"mondo_id","subj":"T46","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A47","pred":"mondo_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A48","pred":"mondo_id","subj":"T48","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"}],"text":"Although the structure of 2 in complex with SARS CoV-1 3CLpro is the final product, the above analysis is expected to apply similarly to the more relevant and structurally close transition state. Accordingly, a focused design strategy aimed at replacing the warhead while retaining the P1 lactam and utilizing the methoxy indole capping group in the early rounds of optimization was initiated. Specifically, an ideal electrophilic warhead would be bioisosteric, with the scissile amide carbonyl of peptidyl substrates ensuring proper alignment within the oxyanion hole of the protease. To better mimic the tetrahedral intermediate generated in the amide bond cleavage, we designed ketone-based covalent reversible and irreversible inhibitors of SARS CoV-1 3CLpro, as illustrated by 3 and 4. Compound 4 was selected as a development candidate for SARS CoV-1 but with the successful public health response that ended the 2003 pandemic, the clinical advancement of 4 was suspended. Following the COVID-19 outbreak, testing has demonstrated that 4 is a potent inhibitor of the SARS CoV-2 3CLpro (Ki = 0.27 ± 0.1 nM) and a cocrystal structure with 4 bound in the active site has been solved. In addition to the potent inhibition of the 3CLpro and viral replication of several coronaviruses, 4 possesses solubility as well as metabolic and chemical stability characteristics, which are consistent with a continuous infusion IV therapeutic treatment for COVID-19. We report the research focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography, which led to the identification of 4 as a molecule warranting further evaluation for its potential to treat coronaviruses, including COVID-19."}

LitCovid-PD-CLO

{"project":"LitCovid-PD-CLO","denotations":[{"id":"T92676","span":{"begin":209,"end":210},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T73055","span":{"begin":211,"end":218},"obj":"http://purl.obolibrary.org/obo/CLO_0009985"},{"id":"T20789","span":{"begin":286,"end":288},"obj":"http://purl.obolibrary.org/obo/CLO_0008285"},{"id":"T9121","span":{"begin":818,"end":819},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T13335","span":{"begin":1012,"end":1019},"obj":"http://purl.obolibrary.org/obo/UBERON_0000473"},{"id":"T88691","span":{"begin":1020,"end":1023},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T27161","span":{"begin":1047,"end":1048},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T90807","span":{"begin":1116,"end":1117},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T52020","span":{"begin":1158,"end":1164},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T76337","span":{"begin":1170,"end":1173},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T86009","span":{"begin":1396,"end":1397},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T73832","span":{"begin":1480,"end":1487},"obj":"http://purl.obolibrary.org/obo/CLO_0009985"},{"id":"T49922","span":{"begin":1691,"end":1692},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"}],"text":"Although the structure of 2 in complex with SARS CoV-1 3CLpro is the final product, the above analysis is expected to apply similarly to the more relevant and structurally close transition state. Accordingly, a focused design strategy aimed at replacing the warhead while retaining the P1 lactam and utilizing the methoxy indole capping group in the early rounds of optimization was initiated. Specifically, an ideal electrophilic warhead would be bioisosteric, with the scissile amide carbonyl of peptidyl substrates ensuring proper alignment within the oxyanion hole of the protease. To better mimic the tetrahedral intermediate generated in the amide bond cleavage, we designed ketone-based covalent reversible and irreversible inhibitors of SARS CoV-1 3CLpro, as illustrated by 3 and 4. Compound 4 was selected as a development candidate for SARS CoV-1 but with the successful public health response that ended the 2003 pandemic, the clinical advancement of 4 was suspended. Following the COVID-19 outbreak, testing has demonstrated that 4 is a potent inhibitor of the SARS CoV-2 3CLpro (Ki = 0.27 ± 0.1 nM) and a cocrystal structure with 4 bound in the active site has been solved. In addition to the potent inhibition of the 3CLpro and viral replication of several coronaviruses, 4 possesses solubility as well as metabolic and chemical stability characteristics, which are consistent with a continuous infusion IV therapeutic treatment for COVID-19. We report the research focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography, which led to the identification of 4 as a molecule warranting further evaluation for its potential to treat coronaviruses, including COVID-19."}

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T6","span":{"begin":1242,"end":1259},"obj":"http://purl.obolibrary.org/obo/GO_0019079"},{"id":"T7","span":{"begin":1242,"end":1259},"obj":"http://purl.obolibrary.org/obo/GO_0019058"}],"text":"Although the structure of 2 in complex with SARS CoV-1 3CLpro is the final product, the above analysis is expected to apply similarly to the more relevant and structurally close transition state. Accordingly, a focused design strategy aimed at replacing the warhead while retaining the P1 lactam and utilizing the methoxy indole capping group in the early rounds of optimization was initiated. Specifically, an ideal electrophilic warhead would be bioisosteric, with the scissile amide carbonyl of peptidyl substrates ensuring proper alignment within the oxyanion hole of the protease. To better mimic the tetrahedral intermediate generated in the amide bond cleavage, we designed ketone-based covalent reversible and irreversible inhibitors of SARS CoV-1 3CLpro, as illustrated by 3 and 4. Compound 4 was selected as a development candidate for SARS CoV-1 but with the successful public health response that ended the 2003 pandemic, the clinical advancement of 4 was suspended. Following the COVID-19 outbreak, testing has demonstrated that 4 is a potent inhibitor of the SARS CoV-2 3CLpro (Ki = 0.27 ± 0.1 nM) and a cocrystal structure with 4 bound in the active site has been solved. In addition to the potent inhibition of the 3CLpro and viral replication of several coronaviruses, 4 possesses solubility as well as metabolic and chemical stability characteristics, which are consistent with a continuous infusion IV therapeutic treatment for COVID-19. We report the research focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography, which led to the identification of 4 as a molecule warranting further evaluation for its potential to treat coronaviruses, including COVID-19."}

LitCovid-sentences

{"project":"LitCovid-sentences","denotations":[{"id":"T41","span":{"begin":0,"end":195},"obj":"Sentence"},{"id":"T42","span":{"begin":196,"end":393},"obj":"Sentence"},{"id":"T43","span":{"begin":394,"end":585},"obj":"Sentence"},{"id":"T44","span":{"begin":586,"end":790},"obj":"Sentence"},{"id":"T45","span":{"begin":791,"end":978},"obj":"Sentence"},{"id":"T46","span":{"begin":979,"end":1186},"obj":"Sentence"},{"id":"T47","span":{"begin":1187,"end":1456},"obj":"Sentence"},{"id":"T48","span":{"begin":1457,"end":1793},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Although the structure of 2 in complex with SARS CoV-1 3CLpro is the final product, the above analysis is expected to apply similarly to the more relevant and structurally close transition state. Accordingly, a focused design strategy aimed at replacing the warhead while retaining the P1 lactam and utilizing the methoxy indole capping group in the early rounds of optimization was initiated. Specifically, an ideal electrophilic warhead would be bioisosteric, with the scissile amide carbonyl of peptidyl substrates ensuring proper alignment within the oxyanion hole of the protease. To better mimic the tetrahedral intermediate generated in the amide bond cleavage, we designed ketone-based covalent reversible and irreversible inhibitors of SARS CoV-1 3CLpro, as illustrated by 3 and 4. Compound 4 was selected as a development candidate for SARS CoV-1 but with the successful public health response that ended the 2003 pandemic, the clinical advancement of 4 was suspended. Following the COVID-19 outbreak, testing has demonstrated that 4 is a potent inhibitor of the SARS CoV-2 3CLpro (Ki = 0.27 ± 0.1 nM) and a cocrystal structure with 4 bound in the active site has been solved. In addition to the potent inhibition of the 3CLpro and viral replication of several coronaviruses, 4 possesses solubility as well as metabolic and chemical stability characteristics, which are consistent with a continuous infusion IV therapeutic treatment for COVID-19. We report the research focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography, which led to the identification of 4 as a molecule warranting further evaluation for its potential to treat coronaviruses, including COVID-19."}

LitCovid-PubTator