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LitCovid-PD-FMA-UBERON

{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T379","span":{"begin":1166,"end":1171},"obj":"Body_part"},{"id":"T380","span":{"begin":2460,"end":2466},"obj":"Body_part"}],"attributes":[{"id":"A379","pred":"fma_id","subj":"T379","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A380","pred":"fma_id","subj":"T380","obj":"http://purl.org/sig/ont/fma/fma62970"}],"text":"MLN4760 is a potent and selective human ACE2 inhibitor (IC50 = 0.44 nM against soluble human ACE2) whose synthesis produces a racemic mixture of two diastereomers that showed 75:25 ratio for Isomer A: Isomer B [113,114] and the purified isomer B is the isomer commercially available from Merck Millipore [114]. Testing MLN-4760 racemic mixture and its isomers, it was observed a concentration-dependent inhibition of recombinant human (rh)ACE or rhACE2 activities with all three inhibitors [114]. The isomer B was less selective (near minimal-maximal rhACE inhibition range 10−6M-10−4M) than the racemate or the isomer A (near minimal-maximal rhACE inhibition range 10−6M-10−2M) and less effective (near maximal rhACE2 inhibition at 10−7M) than the racemate or the isomer A (near maximal rhACE2 inhibition at 10−8 M) for rhACE2 versus rhACE [114]. Moreover, all three inhibitors exerted a significantly higher inhibitory activity against soluble than membrane-bound forms of (m)ACE2 (near maximal mACE2 inhibition at 10−6M), being the isomer B more selective and effective than the racemate or the isomer A for mACE2 vs. mACE expressed on the surface of mononuclear cells (or CD34 hematopoietic progenitors) [114]. A second ACE2 inhibitor, Dx600, produced similar results to those obtained with the isomer B [114]. Another study evaluated the inhibitory activity of both MLN-4760 and DX600 (either the linear conformational form or the disulfide bridged cyclic variant) inhibitors. In this report, the experiments were performed at pH 6.5 [115], a pH at which rhACE2 proteolysis operates at maximal activity [79] and a condition that resembles hypercapnic acidosis which may occur during SARS. MLN-4760 was still able to strongly and specifically inhibit rhACE2 activity (near maximal inhibition at 10−8 M), preventing rhACE2-driven Ang II degradation into Ang (1–7), whereas DX600 (either linear or cyclic variant) inhibits rhACE2 at relatively higher concentration (near maximal inhibition at 10−6 M–10−7 M, respectively) [115]. Altogether these data indicate that the racemate or the isomer A are more effective in inhibiting soluble forms of ACE2 than isomer B and Dx600. Therefore, these inhibitors at opportune (low) concentrations are expected to preferentially reduce systemic sACE2 activity, while preserving the ACE2 activity of (local) membrane-associated forms of ACE2, knowing that catalytic activity of circulating ACE2 was undetectable in human plasma of healthy subjects due to an endogenous ACE2 inhibitor [116]."}

LitCovid-PubTator

LitCovid-PD-MONDO

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T312","span":{"begin":1656,"end":1664},"obj":"Disease"},{"id":"T313","span":{"begin":1688,"end":1692},"obj":"Disease"}],"attributes":[{"id":"A312","pred":"mondo_id","subj":"T312","obj":"http://purl.obolibrary.org/obo/MONDO_0006022"},{"id":"A313","pred":"mondo_id","subj":"T313","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"}],"text":"MLN4760 is a potent and selective human ACE2 inhibitor (IC50 = 0.44 nM against soluble human ACE2) whose synthesis produces a racemic mixture of two diastereomers that showed 75:25 ratio for Isomer A: Isomer B [113,114] and the purified isomer B is the isomer commercially available from Merck Millipore [114]. Testing MLN-4760 racemic mixture and its isomers, it was observed a concentration-dependent inhibition of recombinant human (rh)ACE or rhACE2 activities with all three inhibitors [114]. The isomer B was less selective (near minimal-maximal rhACE inhibition range 10−6M-10−4M) than the racemate or the isomer A (near minimal-maximal rhACE inhibition range 10−6M-10−2M) and less effective (near maximal rhACE2 inhibition at 10−7M) than the racemate or the isomer A (near maximal rhACE2 inhibition at 10−8 M) for rhACE2 versus rhACE [114]. Moreover, all three inhibitors exerted a significantly higher inhibitory activity against soluble than membrane-bound forms of (m)ACE2 (near maximal mACE2 inhibition at 10−6M), being the isomer B more selective and effective than the racemate or the isomer A for mACE2 vs. mACE expressed on the surface of mononuclear cells (or CD34 hematopoietic progenitors) [114]. A second ACE2 inhibitor, Dx600, produced similar results to those obtained with the isomer B [114]. Another study evaluated the inhibitory activity of both MLN-4760 and DX600 (either the linear conformational form or the disulfide bridged cyclic variant) inhibitors. In this report, the experiments were performed at pH 6.5 [115], a pH at which rhACE2 proteolysis operates at maximal activity [79] and a condition that resembles hypercapnic acidosis which may occur during SARS. MLN-4760 was still able to strongly and specifically inhibit rhACE2 activity (near maximal inhibition at 10−8 M), preventing rhACE2-driven Ang II degradation into Ang (1–7), whereas DX600 (either linear or cyclic variant) inhibits rhACE2 at relatively higher concentration (near maximal inhibition at 10−6 M–10−7 M, respectively) [115]. Altogether these data indicate that the racemate or the isomer A are more effective in inhibiting soluble forms of ACE2 than isomer B and Dx600. Therefore, these inhibitors at opportune (low) concentrations are expected to preferentially reduce systemic sACE2 activity, while preserving the ACE2 activity of (local) membrane-associated forms of ACE2, knowing that catalytic activity of circulating ACE2 was undetectable in human plasma of healthy subjects due to an endogenous ACE2 inhibitor [116]."}

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T119","span":{"begin":105,"end":114},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T120","span":{"begin":1567,"end":1578},"obj":"http://purl.obolibrary.org/obo/GO_0006508"},{"id":"T121","span":{"begin":1840,"end":1851},"obj":"http://purl.obolibrary.org/obo/GO_0009056"}],"text":"MLN4760 is a potent and selective human ACE2 inhibitor (IC50 = 0.44 nM against soluble human ACE2) whose synthesis produces a racemic mixture of two diastereomers that showed 75:25 ratio for Isomer A: Isomer B [113,114] and the purified isomer B is the isomer commercially available from Merck Millipore [114]. Testing MLN-4760 racemic mixture and its isomers, it was observed a concentration-dependent inhibition of recombinant human (rh)ACE or rhACE2 activities with all three inhibitors [114]. The isomer B was less selective (near minimal-maximal rhACE inhibition range 10−6M-10−4M) than the racemate or the isomer A (near minimal-maximal rhACE inhibition range 10−6M-10−2M) and less effective (near maximal rhACE2 inhibition at 10−7M) than the racemate or the isomer A (near maximal rhACE2 inhibition at 10−8 M) for rhACE2 versus rhACE [114]. Moreover, all three inhibitors exerted a significantly higher inhibitory activity against soluble than membrane-bound forms of (m)ACE2 (near maximal mACE2 inhibition at 10−6M), being the isomer B more selective and effective than the racemate or the isomer A for mACE2 vs. mACE expressed on the surface of mononuclear cells (or CD34 hematopoietic progenitors) [114]. A second ACE2 inhibitor, Dx600, produced similar results to those obtained with the isomer B [114]. Another study evaluated the inhibitory activity of both MLN-4760 and DX600 (either the linear conformational form or the disulfide bridged cyclic variant) inhibitors. In this report, the experiments were performed at pH 6.5 [115], a pH at which rhACE2 proteolysis operates at maximal activity [79] and a condition that resembles hypercapnic acidosis which may occur during SARS. MLN-4760 was still able to strongly and specifically inhibit rhACE2 activity (near maximal inhibition at 10−8 M), preventing rhACE2-driven Ang II degradation into Ang (1–7), whereas DX600 (either linear or cyclic variant) inhibits rhACE2 at relatively higher concentration (near maximal inhibition at 10−6 M–10−7 M, respectively) [115]. Altogether these data indicate that the racemate or the isomer A are more effective in inhibiting soluble forms of ACE2 than isomer B and Dx600. Therefore, these inhibitors at opportune (low) concentrations are expected to preferentially reduce systemic sACE2 activity, while preserving the ACE2 activity of (local) membrane-associated forms of ACE2, knowing that catalytic activity of circulating ACE2 was undetectable in human plasma of healthy subjects due to an endogenous ACE2 inhibitor [116]."}

LitCovid-sentences

{"project":"LitCovid-sentences","denotations":[{"id":"T270","span":{"begin":0,"end":200},"obj":"Sentence"},{"id":"T271","span":{"begin":201,"end":310},"obj":"Sentence"},{"id":"T272","span":{"begin":311,"end":496},"obj":"Sentence"},{"id":"T273","span":{"begin":497,"end":847},"obj":"Sentence"},{"id":"T274","span":{"begin":848,"end":1214},"obj":"Sentence"},{"id":"T275","span":{"begin":1215,"end":1314},"obj":"Sentence"},{"id":"T276","span":{"begin":1315,"end":1481},"obj":"Sentence"},{"id":"T277","span":{"begin":1482,"end":1693},"obj":"Sentence"},{"id":"T278","span":{"begin":1694,"end":2030},"obj":"Sentence"},{"id":"T279","span":{"begin":2031,"end":2175},"obj":"Sentence"},{"id":"T280","span":{"begin":2176,"end":2529},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"MLN4760 is a potent and selective human ACE2 inhibitor (IC50 = 0.44 nM against soluble human ACE2) whose synthesis produces a racemic mixture of two diastereomers that showed 75:25 ratio for Isomer A: Isomer B [113,114] and the purified isomer B is the isomer commercially available from Merck Millipore [114]. Testing MLN-4760 racemic mixture and its isomers, it was observed a concentration-dependent inhibition of recombinant human (rh)ACE or rhACE2 activities with all three inhibitors [114]. The isomer B was less selective (near minimal-maximal rhACE inhibition range 10−6M-10−4M) than the racemate or the isomer A (near minimal-maximal rhACE inhibition range 10−6M-10−2M) and less effective (near maximal rhACE2 inhibition at 10−7M) than the racemate or the isomer A (near maximal rhACE2 inhibition at 10−8 M) for rhACE2 versus rhACE [114]. Moreover, all three inhibitors exerted a significantly higher inhibitory activity against soluble than membrane-bound forms of (m)ACE2 (near maximal mACE2 inhibition at 10−6M), being the isomer B more selective and effective than the racemate or the isomer A for mACE2 vs. mACE expressed on the surface of mononuclear cells (or CD34 hematopoietic progenitors) [114]. A second ACE2 inhibitor, Dx600, produced similar results to those obtained with the isomer B [114]. Another study evaluated the inhibitory activity of both MLN-4760 and DX600 (either the linear conformational form or the disulfide bridged cyclic variant) inhibitors. In this report, the experiments were performed at pH 6.5 [115], a pH at which rhACE2 proteolysis operates at maximal activity [79] and a condition that resembles hypercapnic acidosis which may occur during SARS. MLN-4760 was still able to strongly and specifically inhibit rhACE2 activity (near maximal inhibition at 10−8 M), preventing rhACE2-driven Ang II degradation into Ang (1–7), whereas DX600 (either linear or cyclic variant) inhibits rhACE2 at relatively higher concentration (near maximal inhibition at 10−6 M–10−7 M, respectively) [115]. Altogether these data indicate that the racemate or the isomer A are more effective in inhibiting soluble forms of ACE2 than isomer B and Dx600. Therefore, these inhibitors at opportune (low) concentrations are expected to preferentially reduce systemic sACE2 activity, while preserving the ACE2 activity of (local) membrane-associated forms of ACE2, knowing that catalytic activity of circulating ACE2 was undetectable in human plasma of healthy subjects due to an endogenous ACE2 inhibitor [116]."}

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T93","span":{"begin":1656,"end":1664},"obj":"Phenotype"}],"attributes":[{"id":"A93","pred":"hp_id","subj":"T93","obj":"http://purl.obolibrary.org/obo/HP_0001941"}],"text":"MLN4760 is a potent and selective human ACE2 inhibitor (IC50 = 0.44 nM against soluble human ACE2) whose synthesis produces a racemic mixture of two diastereomers that showed 75:25 ratio for Isomer A: Isomer B [113,114] and the purified isomer B is the isomer commercially available from Merck Millipore [114]. Testing MLN-4760 racemic mixture and its isomers, it was observed a concentration-dependent inhibition of recombinant human (rh)ACE or rhACE2 activities with all three inhibitors [114]. The isomer B was less selective (near minimal-maximal rhACE inhibition range 10−6M-10−4M) than the racemate or the isomer A (near minimal-maximal rhACE inhibition range 10−6M-10−2M) and less effective (near maximal rhACE2 inhibition at 10−7M) than the racemate or the isomer A (near maximal rhACE2 inhibition at 10−8 M) for rhACE2 versus rhACE [114]. Moreover, all three inhibitors exerted a significantly higher inhibitory activity against soluble than membrane-bound forms of (m)ACE2 (near maximal mACE2 inhibition at 10−6M), being the isomer B more selective and effective than the racemate or the isomer A for mACE2 vs. mACE expressed on the surface of mononuclear cells (or CD34 hematopoietic progenitors) [114]. A second ACE2 inhibitor, Dx600, produced similar results to those obtained with the isomer B [114]. Another study evaluated the inhibitory activity of both MLN-4760 and DX600 (either the linear conformational form or the disulfide bridged cyclic variant) inhibitors. In this report, the experiments were performed at pH 6.5 [115], a pH at which rhACE2 proteolysis operates at maximal activity [79] and a condition that resembles hypercapnic acidosis which may occur during SARS. MLN-4760 was still able to strongly and specifically inhibit rhACE2 activity (near maximal inhibition at 10−8 M), preventing rhACE2-driven Ang II degradation into Ang (1–7), whereas DX600 (either linear or cyclic variant) inhibits rhACE2 at relatively higher concentration (near maximal inhibition at 10−6 M–10−7 M, respectively) [115]. Altogether these data indicate that the racemate or the isomer A are more effective in inhibiting soluble forms of ACE2 than isomer B and Dx600. Therefore, these inhibitors at opportune (low) concentrations are expected to preferentially reduce systemic sACE2 activity, while preserving the ACE2 activity of (local) membrane-associated forms of ACE2, knowing that catalytic activity of circulating ACE2 was undetectable in human plasma of healthy subjects due to an endogenous ACE2 inhibitor [116]."}

2_test

{"project":"2_test","denotations":[{"id":"32708755-12358520-20678851","span":{"begin":211,"end":214},"obj":"12358520"},{"id":"32708755-26851370-20678852","span":{"begin":215,"end":218},"obj":"26851370"},{"id":"32708755-26851370-20678853","span":{"begin":305,"end":308},"obj":"26851370"},{"id":"32708755-26851370-20678854","span":{"begin":491,"end":494},"obj":"26851370"},{"id":"32708755-26851370-20678855","span":{"begin":842,"end":845},"obj":"26851370"},{"id":"32708755-26851370-20678856","span":{"begin":1209,"end":1212},"obj":"26851370"},{"id":"32708755-26851370-20678857","span":{"begin":1309,"end":1312},"obj":"26851370"},{"id":"32708755-22777933-20678858","span":{"begin":1540,"end":1543},"obj":"22777933"},{"id":"32708755-22777933-20678859","span":{"begin":2025,"end":2028},"obj":"22777933"},{"id":"32708755-18223027-20678860","span":{"begin":2524,"end":2527},"obj":"18223027"}],"text":"MLN4760 is a potent and selective human ACE2 inhibitor (IC50 = 0.44 nM against soluble human ACE2) whose synthesis produces a racemic mixture of two diastereomers that showed 75:25 ratio for Isomer A: Isomer B [113,114] and the purified isomer B is the isomer commercially available from Merck Millipore [114]. Testing MLN-4760 racemic mixture and its isomers, it was observed a concentration-dependent inhibition of recombinant human (rh)ACE or rhACE2 activities with all three inhibitors [114]. The isomer B was less selective (near minimal-maximal rhACE inhibition range 10−6M-10−4M) than the racemate or the isomer A (near minimal-maximal rhACE inhibition range 10−6M-10−2M) and less effective (near maximal rhACE2 inhibition at 10−7M) than the racemate or the isomer A (near maximal rhACE2 inhibition at 10−8 M) for rhACE2 versus rhACE [114]. Moreover, all three inhibitors exerted a significantly higher inhibitory activity against soluble than membrane-bound forms of (m)ACE2 (near maximal mACE2 inhibition at 10−6M), being the isomer B more selective and effective than the racemate or the isomer A for mACE2 vs. mACE expressed on the surface of mononuclear cells (or CD34 hematopoietic progenitors) [114]. A second ACE2 inhibitor, Dx600, produced similar results to those obtained with the isomer B [114]. Another study evaluated the inhibitory activity of both MLN-4760 and DX600 (either the linear conformational form or the disulfide bridged cyclic variant) inhibitors. In this report, the experiments were performed at pH 6.5 [115], a pH at which rhACE2 proteolysis operates at maximal activity [79] and a condition that resembles hypercapnic acidosis which may occur during SARS. MLN-4760 was still able to strongly and specifically inhibit rhACE2 activity (near maximal inhibition at 10−8 M), preventing rhACE2-driven Ang II degradation into Ang (1–7), whereas DX600 (either linear or cyclic variant) inhibits rhACE2 at relatively higher concentration (near maximal inhibition at 10−6 M–10−7 M, respectively) [115]. Altogether these data indicate that the racemate or the isomer A are more effective in inhibiting soluble forms of ACE2 than isomer B and Dx600. Therefore, these inhibitors at opportune (low) concentrations are expected to preferentially reduce systemic sACE2 activity, while preserving the ACE2 activity of (local) membrane-associated forms of ACE2, knowing that catalytic activity of circulating ACE2 was undetectable in human plasma of healthy subjects due to an endogenous ACE2 inhibitor [116]."}

PMC:7408073 / 55819-58348 JSONTXT

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PMC:7408073 / 55819-58348 JSON TXT