PMC:7795856 / 16963-18919 JSONTXT

{"project":"LitCovid-PubTator","denotations":[{"id":"302","span":{"begin":52,"end":55},"obj":"Gene"},{"id":"303","span":{"begin":426,"end":439},"obj":"Gene"},{"id":"304","span":{"begin":504,"end":507},"obj":"Gene"},{"id":"305","span":{"begin":790,"end":793},"obj":"Gene"},{"id":"306","span":{"begin":1597,"end":1600},"obj":"Gene"},{"id":"307","span":{"begin":1710,"end":1713},"obj":"Gene"},{"id":"308","span":{"begin":1842,"end":1845},"obj":"Gene"},{"id":"309","span":{"begin":222,"end":226},"obj":"Species"},{"id":"310","span":{"begin":420,"end":425},"obj":"Species"},{"id":"311","span":{"begin":18,"end":21},"obj":"Chemical"},{"id":"312","span":{"begin":276,"end":283},"obj":"Chemical"},{"id":"313","span":{"begin":698,"end":732},"obj":"Chemical"},{"id":"314","span":{"begin":605,"end":610},"obj":"Disease"},{"id":"315","span":{"begin":1634,"end":1640},"obj":"Disease"}],"attributes":[{"id":"A302","pred":"tao:has_database_id","subj":"302","obj":"Gene:134864"},{"id":"A303","pred":"tao:has_database_id","subj":"303","obj":"Gene:213"},{"id":"A304","pred":"tao:has_database_id","subj":"304","obj":"Gene:134864"},{"id":"A305","pred":"tao:has_database_id","subj":"305","obj":"Gene:134864"},{"id":"A306","pred":"tao:has_database_id","subj":"306","obj":"Gene:134864"},{"id":"A307","pred":"tao:has_database_id","subj":"307","obj":"Gene:134864"},{"id":"A308","pred":"tao:has_database_id","subj":"308","obj":"Gene:134864"},{"id":"A309","pred":"tao:has_database_id","subj":"309","obj":"Tax:10116"},{"id":"A310","pred":"tao:has_database_id","subj":"310","obj":"Tax:9606"},{"id":"A314","pred":"tao:has_database_id","subj":"314","obj":"MESH:D009369"},{"id":"A315","pred":"tao:has_database_id","subj":"315","obj":"MESH:D009369"}],"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":"Attachment of the PAS sequence at either end of the Tα1 peptide increased the hydrodynamic volume by more than an order of magnitude as shown by SEC. This strongly expanded molecular size resulted in a plasma half-life in rats of around 16 h after a subcutaneous injection of Tα1-PAS, which is more than an 8-fold increase compared to the unmodified peptide drug (1.9 h) [41]. Based on in vitro cell culture assays with human serum albumin fusion proteins [49], both the C-terminus and the N-terminus of Tα1 should be permissible to modification while retaining bioactivity. This was also shown in animal tumor models for C-terminal fusion with an immunoglobulin Fc fragment [41], an internalizing arginylglycylaspartic acid peptide iRGD [50], and thymopentin [51]. However, in the case of Tα1, some caution is appropriate regarding the significance of in vitro cell culture assays as its mode of action is complex and involves different receptors provoking multiple biological effects on various cell types [52]. Second, a prolonged circulation in the body as demonstrated here via application of the PASylation technology influences both binding kinetics and bioactivity, which is not reflected in vitro. While attachment of large macromolecules, such as PAS polypeptides or albumin, but also PEG [53], can lead to lower receptor association rates for bioactive peptides or proteins, this is usually overcompensated by the drastically prolonged in vivo half-life, which results in a strongly enhanced bioactivity as demonstrated for multiple PASylated biopharmaceuticals [37,54]. In the case of Tα1, superior effects in preclinical cancer models due to prolonged circulation were recently demonstrated for a Tα1-Fc fusion protein [41,44]. Such studies would be the obvious next step to investigate enhanced in vivo bioactivity of PASylated Tα1, and it will be interesting to see whether its N-terminally or C-terminally PASylated version performs better."}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T15","span":{"begin":605,"end":610},"obj":"Phenotype"},{"id":"T16","span":{"begin":1634,"end":1640},"obj":"Phenotype"}],"attributes":[{"id":"A15","pred":"hp_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A16","pred":"hp_id","subj":"T16","obj":"http://purl.obolibrary.org/obo/HP_0002664"}],"text":"Attachment of the PAS sequence at either end of the Tα1 peptide increased the hydrodynamic volume by more than an order of magnitude as shown by SEC. This strongly expanded molecular size resulted in a plasma half-life in rats of around 16 h after a subcutaneous injection of Tα1-PAS, which is more than an 8-fold increase compared to the unmodified peptide drug (1.9 h) [41]. Based on in vitro cell culture assays with human serum albumin fusion proteins [49], both the C-terminus and the N-terminus of Tα1 should be permissible to modification while retaining bioactivity. This was also shown in animal tumor models for C-terminal fusion with an immunoglobulin Fc fragment [41], an internalizing arginylglycylaspartic acid peptide iRGD [50], and thymopentin [51]. However, in the case of Tα1, some caution is appropriate regarding the significance of in vitro cell culture assays as its mode of action is complex and involves different receptors provoking multiple biological effects on various cell types [52]. Second, a prolonged circulation in the body as demonstrated here via application of the PASylation technology influences both binding kinetics and bioactivity, which is not reflected in vitro. While attachment of large macromolecules, such as PAS polypeptides or albumin, but also PEG [53], can lead to lower receptor association rates for bioactive peptides or proteins, this is usually overcompensated by the drastically prolonged in vivo half-life, which results in a strongly enhanced bioactivity as demonstrated for multiple PASylated biopharmaceuticals [37,54]. In the case of Tα1, superior effects in preclinical cancer models due to prolonged circulation were recently demonstrated for a Tα1-Fc fusion protein [41,44]. Such studies would be the obvious next step to investigate enhanced in vivo bioactivity of PASylated Tα1, and it will be interesting to see whether its N-terminally or C-terminally PASylated version performs better."}

{"project":"LitCovid-sentences","denotations":[{"id":"T100","span":{"begin":0,"end":149},"obj":"Sentence"},{"id":"T101","span":{"begin":150,"end":376},"obj":"Sentence"},{"id":"T102","span":{"begin":377,"end":574},"obj":"Sentence"},{"id":"T103","span":{"begin":575,"end":765},"obj":"Sentence"},{"id":"T104","span":{"begin":766,"end":1013},"obj":"Sentence"},{"id":"T105","span":{"begin":1014,"end":1206},"obj":"Sentence"},{"id":"T106","span":{"begin":1207,"end":1581},"obj":"Sentence"},{"id":"T107","span":{"begin":1582,"end":1740},"obj":"Sentence"},{"id":"T108","span":{"begin":1741,"end":1956},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Attachment of the PAS sequence at either end of the Tα1 peptide increased the hydrodynamic volume by more than an order of magnitude as shown by SEC. This strongly expanded molecular size resulted in a plasma half-life in rats of around 16 h after a subcutaneous injection of Tα1-PAS, which is more than an 8-fold increase compared to the unmodified peptide drug (1.9 h) [41]. Based on in vitro cell culture assays with human serum albumin fusion proteins [49], both the C-terminus and the N-terminus of Tα1 should be permissible to modification while retaining bioactivity. This was also shown in animal tumor models for C-terminal fusion with an immunoglobulin Fc fragment [41], an internalizing arginylglycylaspartic acid peptide iRGD [50], and thymopentin [51]. However, in the case of Tα1, some caution is appropriate regarding the significance of in vitro cell culture assays as its mode of action is complex and involves different receptors provoking multiple biological effects on various cell types [52]. Second, a prolonged circulation in the body as demonstrated here via application of the PASylation technology influences both binding kinetics and bioactivity, which is not reflected in vitro. While attachment of large macromolecules, such as PAS polypeptides or albumin, but also PEG [53], can lead to lower receptor association rates for bioactive peptides or proteins, this is usually overcompensated by the drastically prolonged in vivo half-life, which results in a strongly enhanced bioactivity as demonstrated for multiple PASylated biopharmaceuticals [37,54]. In the case of Tα1, superior effects in preclinical cancer models due to prolonged circulation were recently demonstrated for a Tα1-Fc fusion protein [41,44]. Such studies would be the obvious next step to investigate enhanced in vivo bioactivity of PASylated Tα1, and it will be interesting to see whether its N-terminally or C-terminally PASylated version performs better."}