N-terminal mono-PEGylation of growth hormone antagonist: Correlation of PEG size and pharmacodynamic behavior
Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the p...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Wu, Ling [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2013transfer abstract |
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| Schlagwörter: |
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| Umfang: |
8 |
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| Übergeordnetes Werk: |
Enthalten in: Description d’une cohorte française multicentrique de porteurs asymptomatiques d’anticorps anti-phospholipides - Nigolian, H. ELSEVIER, 2022, New York, NY [u.a.] |
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| Übergeordnetes Werk: |
volume:453 ; year:2013 ; number:2 ; day:10 ; month:09 ; pages:533-540 ; extent:8 |
| Links: |
|---|
| DOI / URN: |
10.1016/j.ijpharm.2013.06.022 |
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| 520 | |a Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. | ||
| 520 | |a Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. | ||
| 650 | 7 | |a N-terminus |2 Elsevier | |
| 650 | 7 | |a PEGylation |2 Elsevier | |
| 650 | 7 | |a Polyethylene glycol |2 Elsevier | |
| 650 | 7 | |a Acromegaly |2 Elsevier | |
| 650 | 7 | |a Growth hormone antagonist |2 Elsevier | |
| 700 | 1 | |a Ho, Sa V. |4 oth | |
| 700 | 1 | |a Wang, Wei |4 oth | |
| 700 | 1 | |a Gao, Jianping |4 oth | |
| 700 | 1 | |a Zhang, Guifeng |4 oth | |
| 700 | 1 | |a Su, Zhiguo |4 oth | |
| 700 | 1 | |a Hu, Tao |4 oth | |
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10.1016/j.ijpharm.2013.06.022 doi GBVA2013012000021.pica (DE-627)ELV033145695 (ELSEVIER)S0378-5173(13)00531-0 DE-627 ger DE-627 rakwb eng 610 610 DE-600 610 VZ 44.61 bkl Wu, Ling verfasserin aut N-terminal mono-PEGylation of growth hormone antagonist: Correlation of PEG size and pharmacodynamic behavior 2013transfer abstract 8 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. N-terminus Elsevier PEGylation Elsevier Polyethylene glycol Elsevier Acromegaly Elsevier Growth hormone antagonist Elsevier Ho, Sa V. oth Wang, Wei oth Gao, Jianping oth Zhang, Guifeng oth Su, Zhiguo oth Hu, Tao oth Enthalten in Elsevier Nigolian, H. ELSEVIER Description d’une cohorte française multicentrique de porteurs asymptomatiques d’anticorps anti-phospholipides 2022 New York, NY [u.a.] (DE-627)ELV008932840 volume:453 year:2013 number:2 day:10 month:09 pages:533-540 extent:8 https://doi.org/10.1016/j.ijpharm.2013.06.022 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 44.61 Innere Medizin VZ AR 453 2013 2 10 0910 533-540 8 045F 610 |
| spelling |
10.1016/j.ijpharm.2013.06.022 doi GBVA2013012000021.pica (DE-627)ELV033145695 (ELSEVIER)S0378-5173(13)00531-0 DE-627 ger DE-627 rakwb eng 610 610 DE-600 610 VZ 44.61 bkl Wu, Ling verfasserin aut N-terminal mono-PEGylation of growth hormone antagonist: Correlation of PEG size and pharmacodynamic behavior 2013transfer abstract 8 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. N-terminus Elsevier PEGylation Elsevier Polyethylene glycol Elsevier Acromegaly Elsevier Growth hormone antagonist Elsevier Ho, Sa V. oth Wang, Wei oth Gao, Jianping oth Zhang, Guifeng oth Su, Zhiguo oth Hu, Tao oth Enthalten in Elsevier Nigolian, H. ELSEVIER Description d’une cohorte française multicentrique de porteurs asymptomatiques d’anticorps anti-phospholipides 2022 New York, NY [u.a.] (DE-627)ELV008932840 volume:453 year:2013 number:2 day:10 month:09 pages:533-540 extent:8 https://doi.org/10.1016/j.ijpharm.2013.06.022 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 44.61 Innere Medizin VZ AR 453 2013 2 10 0910 533-540 8 045F 610 |
| allfields_unstemmed |
10.1016/j.ijpharm.2013.06.022 doi GBVA2013012000021.pica (DE-627)ELV033145695 (ELSEVIER)S0378-5173(13)00531-0 DE-627 ger DE-627 rakwb eng 610 610 DE-600 610 VZ 44.61 bkl Wu, Ling verfasserin aut N-terminal mono-PEGylation of growth hormone antagonist: Correlation of PEG size and pharmacodynamic behavior 2013transfer abstract 8 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. N-terminus Elsevier PEGylation Elsevier Polyethylene glycol Elsevier Acromegaly Elsevier Growth hormone antagonist Elsevier Ho, Sa V. oth Wang, Wei oth Gao, Jianping oth Zhang, Guifeng oth Su, Zhiguo oth Hu, Tao oth Enthalten in Elsevier Nigolian, H. ELSEVIER Description d’une cohorte française multicentrique de porteurs asymptomatiques d’anticorps anti-phospholipides 2022 New York, NY [u.a.] (DE-627)ELV008932840 volume:453 year:2013 number:2 day:10 month:09 pages:533-540 extent:8 https://doi.org/10.1016/j.ijpharm.2013.06.022 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 44.61 Innere Medizin VZ AR 453 2013 2 10 0910 533-540 8 045F 610 |
| allfieldsGer |
10.1016/j.ijpharm.2013.06.022 doi GBVA2013012000021.pica (DE-627)ELV033145695 (ELSEVIER)S0378-5173(13)00531-0 DE-627 ger DE-627 rakwb eng 610 610 DE-600 610 VZ 44.61 bkl Wu, Ling verfasserin aut N-terminal mono-PEGylation of growth hormone antagonist: Correlation of PEG size and pharmacodynamic behavior 2013transfer abstract 8 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. N-terminus Elsevier PEGylation Elsevier Polyethylene glycol Elsevier Acromegaly Elsevier Growth hormone antagonist Elsevier Ho, Sa V. oth Wang, Wei oth Gao, Jianping oth Zhang, Guifeng oth Su, Zhiguo oth Hu, Tao oth Enthalten in Elsevier Nigolian, H. ELSEVIER Description d’une cohorte française multicentrique de porteurs asymptomatiques d’anticorps anti-phospholipides 2022 New York, NY [u.a.] (DE-627)ELV008932840 volume:453 year:2013 number:2 day:10 month:09 pages:533-540 extent:8 https://doi.org/10.1016/j.ijpharm.2013.06.022 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 44.61 Innere Medizin VZ AR 453 2013 2 10 0910 533-540 8 045F 610 |
| allfieldsSound |
10.1016/j.ijpharm.2013.06.022 doi GBVA2013012000021.pica (DE-627)ELV033145695 (ELSEVIER)S0378-5173(13)00531-0 DE-627 ger DE-627 rakwb eng 610 610 DE-600 610 VZ 44.61 bkl Wu, Ling verfasserin aut N-terminal mono-PEGylation of growth hormone antagonist: Correlation of PEG size and pharmacodynamic behavior 2013transfer abstract 8 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. N-terminus Elsevier PEGylation Elsevier Polyethylene glycol Elsevier Acromegaly Elsevier Growth hormone antagonist Elsevier Ho, Sa V. oth Wang, Wei oth Gao, Jianping oth Zhang, Guifeng oth Su, Zhiguo oth Hu, Tao oth Enthalten in Elsevier Nigolian, H. ELSEVIER Description d’une cohorte française multicentrique de porteurs asymptomatiques d’anticorps anti-phospholipides 2022 New York, NY [u.a.] (DE-627)ELV008932840 volume:453 year:2013 number:2 day:10 month:09 pages:533-540 extent:8 https://doi.org/10.1016/j.ijpharm.2013.06.022 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 44.61 Innere Medizin VZ AR 453 2013 2 10 0910 533-540 8 045F 610 |
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Enthalten in Description d’une cohorte française multicentrique de porteurs asymptomatiques d’anticorps anti-phospholipides New York, NY [u.a.] volume:453 year:2013 number:2 day:10 month:09 pages:533-540 extent:8 |
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Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. |
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Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. |
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Abstract Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15–20min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20kDa and 40kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40kDa PEG was more efficient than 20kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30–43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA. |
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