Abstract
The use of therapeutic proteins is often impaired by their short in vivo half-lives. PEGylation has been exploited to enhance protein stability and to prolong the pharmacokinetic. The biophysical characterization of two site-specific mono-PEGylated forms of human growth hormone (hGH) - chemically N-terminal PEGylated hGH (PEG-Nter-hGH) and enzymatically Gln141 PEGylated hGH (PEG-Gln141-hGH) via transglutaminase - is outlined here and their pharmacodynamics are compared. The thermal stability of PEG-Nter-hGH was increased with respect to that of hGH and PEG-Gln141-hGH. Pharmacodynamic studies in rats showed that a single injection of the conjugates had a better or comparable potency with respect to a daily hGH on a week schedule in terms of weight gain, femoral length, and tibial diaphysis width. Two different site-specific monoPEGylated forms of hGH are prepared using a chemical, N-terminal PEGylation and enzymatic, transglutaminase-based conjugation approaches. The N-terminal PEGylation yielded a conjugate with a higher thermal stability and, of particular interest, one that is able to recover the secondary structure after thermal denaturation.
| Original language | English |
|---|---|
| Pages (from-to) | 50-56 |
| Number of pages | 7 |
| Journal | Macromolecular Bioscience |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 1 2016 |
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Keywords
- enzymatic PEGylation
- hGH
- PEGylation
- transglutaminase
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Biomaterials
- Polymers and Plastics
- Materials Chemistry
Cite this
Chemical and Enzymatic Site Specific PEGylation of hGH : The Stability and in vivo Activity of PEG-N-Terminal-hGH and PEG-Gln141-hGH Conjugates. / Grigoletto, Antonella; Mero, Anna; Zanusso, Ilenia; Schiavon, Oddone; Pasut, Gianfranco.
In: Macromolecular Bioscience, Vol. 16, No. 1, 01.01.2016, p. 50-56.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chemical and Enzymatic Site Specific PEGylation of hGH
T2 - The Stability and in vivo Activity of PEG-N-Terminal-hGH and PEG-Gln141-hGH Conjugates
AU - Grigoletto, Antonella
AU - Mero, Anna
AU - Zanusso, Ilenia
AU - Schiavon, Oddone
AU - Pasut, Gianfranco
PY - 2016/1/1
Y1 - 2016/1/1
N2 - The use of therapeutic proteins is often impaired by their short in vivo half-lives. PEGylation has been exploited to enhance protein stability and to prolong the pharmacokinetic. The biophysical characterization of two site-specific mono-PEGylated forms of human growth hormone (hGH) - chemically N-terminal PEGylated hGH (PEG-Nter-hGH) and enzymatically Gln141 PEGylated hGH (PEG-Gln141-hGH) via transglutaminase - is outlined here and their pharmacodynamics are compared. The thermal stability of PEG-Nter-hGH was increased with respect to that of hGH and PEG-Gln141-hGH. Pharmacodynamic studies in rats showed that a single injection of the conjugates had a better or comparable potency with respect to a daily hGH on a week schedule in terms of weight gain, femoral length, and tibial diaphysis width. Two different site-specific monoPEGylated forms of hGH are prepared using a chemical, N-terminal PEGylation and enzymatic, transglutaminase-based conjugation approaches. The N-terminal PEGylation yielded a conjugate with a higher thermal stability and, of particular interest, one that is able to recover the secondary structure after thermal denaturation.
AB - The use of therapeutic proteins is often impaired by their short in vivo half-lives. PEGylation has been exploited to enhance protein stability and to prolong the pharmacokinetic. The biophysical characterization of two site-specific mono-PEGylated forms of human growth hormone (hGH) - chemically N-terminal PEGylated hGH (PEG-Nter-hGH) and enzymatically Gln141 PEGylated hGH (PEG-Gln141-hGH) via transglutaminase - is outlined here and their pharmacodynamics are compared. The thermal stability of PEG-Nter-hGH was increased with respect to that of hGH and PEG-Gln141-hGH. Pharmacodynamic studies in rats showed that a single injection of the conjugates had a better or comparable potency with respect to a daily hGH on a week schedule in terms of weight gain, femoral length, and tibial diaphysis width. Two different site-specific monoPEGylated forms of hGH are prepared using a chemical, N-terminal PEGylation and enzymatic, transglutaminase-based conjugation approaches. The N-terminal PEGylation yielded a conjugate with a higher thermal stability and, of particular interest, one that is able to recover the secondary structure after thermal denaturation.
KW - enzymatic PEGylation
KW - hGH
KW - PEGylation
KW - transglutaminase
UR - http://www.scopus.com/inward/record.url?scp=84954376903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954376903&partnerID=8YFLogxK
U2 - 10.1002/mabi.201500282
DO - 10.1002/mabi.201500282
M3 - Article
VL - 16
SP - 50
EP - 56
JO - Macromolecular Bioscience
JF - Macromolecular Bioscience
SN - 1616-5187
IS - 1
ER -