PMC:7795856 / 115-1524 JSONTXT

{"project":"LitCovid-PubTator","denotations":[{"id":"18","span":{"begin":13,"end":16},"obj":"Gene"},{"id":"19","span":{"begin":533,"end":536},"obj":"Gene"},{"id":"20","span":{"begin":71,"end":88},"obj":"Species"},{"id":"21","span":{"begin":540,"end":556},"obj":"Species"},{"id":"22","span":{"begin":903,"end":907},"obj":"Species"},{"id":"23","span":{"begin":966,"end":975},"obj":"Species"},{"id":"24","span":{"begin":90,"end":93},"obj":"Species"},{"id":"25","span":{"begin":475,"end":476},"obj":"Chemical"},{"id":"26","span":{"begin":492,"end":496},"obj":"Chemical"},{"id":"27","span":{"begin":810,"end":813},"obj":"Chemical"},{"id":"28","span":{"begin":814,"end":817},"obj":"Chemical"},{"id":"29","span":{"begin":818,"end":821},"obj":"Chemical"},{"id":"30","span":{"begin":823,"end":826},"obj":"Chemical"},{"id":"31","span":{"begin":99,"end":133},"obj":"Disease"},{"id":"32","span":{"begin":212,"end":220},"obj":"Disease"},{"id":"33","span":{"begin":221,"end":231},"obj":"Disease"},{"id":"34","span":{"begin":236,"end":242},"obj":"Disease"},{"id":"35","span":{"begin":991,"end":1006},"obj":"Disease"}],"attributes":[{"id":"A18","pred":"tao:has_database_id","subj":"18","obj":"Gene:134864"},{"id":"A19","pred":"tao:has_database_id","subj":"19","obj":"Gene:134864"},{"id":"A20","pred":"tao:has_database_id","subj":"20","obj":"Tax:10407"},{"id":"A21","pred":"tao:has_database_id","subj":"21","obj":"Tax:562"},{"id":"A22","pred":"tao:has_database_id","subj":"22","obj":"Tax:10116"},{"id":"A23","pred":"tao:has_database_id","subj":"23","obj":"Tax:2005392"},{"id":"A24","pred":"tao:has_database_id","subj":"24","obj":"Tax:10407"},{"id":"A25","pred":"tao:has_database_id","subj":"25","obj":"MESH:D009584"},{"id":"A27","pred":"tao:has_database_id","subj":"27","obj":"MESH:D011392"},{"id":"A28","pred":"tao:has_database_id","subj":"28","obj":"MESH:D000409"},{"id":"A29","pred":"tao:has_database_id","subj":"29","obj":"MESH:D012694"},{"id":"A31","pred":"tao:has_database_id","subj":"31","obj":"MESH:D006526"},{"id":"A32","pred":"tao:has_database_id","subj":"32","obj":"MESH:C000657245"},{"id":"A33","pred":"tao:has_database_id","subj":"33","obj":"MESH:D007239"},{"id":"A34","pred":"tao:has_database_id","subj":"34","obj":"MESH:D009369"},{"id":"A35","pred":"tao:has_database_id","subj":"35","obj":"MESH:D007674"}],"namespaces":[{"prefix":"Tax","uri":"https://www.ncbi.nlm.nih.gov/taxonomy/"},{"prefix":"MESH","uri":"https://id.nlm.nih.gov/mesh/"},{"prefix":"Gene","uri":"https://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"CVCL","uri":"https://web.expasy.org/cellosaurus/CVCL_"}],"text":"Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in Escherichia coli at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance."}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T2","span":{"begin":71,"end":80},"obj":"Phenotype"},{"id":"T3","span":{"begin":99,"end":108},"obj":"Phenotype"},{"id":"T4","span":{"begin":236,"end":242},"obj":"Phenotype"}],"attributes":[{"id":"A2","pred":"hp_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/HP_0012115"},{"id":"A3","pred":"hp_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/HP_0012115"},{"id":"A4","pred":"hp_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/HP_0002664"}],"text":"Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in Escherichia coli at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance."}

{"project":"LitCovid-sentences","denotations":[{"id":"T4","span":{"begin":0,"end":243},"obj":"Sentence"},{"id":"T5","span":{"begin":244,"end":407},"obj":"Sentence"},{"id":"T6","span":{"begin":408,"end":571},"obj":"Sentence"},{"id":"T7","span":{"begin":572,"end":687},"obj":"Sentence"},{"id":"T8","span":{"begin":688,"end":856},"obj":"Sentence"},{"id":"T9","span":{"begin":857,"end":1018},"obj":"Sentence"},{"id":"T10","span":{"begin":1019,"end":1136},"obj":"Sentence"},{"id":"T11","span":{"begin":1137,"end":1409},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in Escherichia coli at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance."}