Growth hormone antagonist (GHA) is an analog of growth hormone (GH) which has been widely used to treat acromegaly because it can inhibit GH action by interruption of growth hormone receptor (GHR)-linked signal transduction.

 However, GHA has a short plasma half-life of 15-20 min following subcutaneous injection, which has limited its clinical application. Previous study reported that PEGylation, chemical conjugation with polyethylene glycol (PEG) was an effective method to solve the problem and had been used to improve the therapeutic potentials of GHA.

 It is known that the bioactivity of GHA would decreased when conjugation of large PEG molecule due to the steric shielding effect of PEG. Researchers with Institute of Process Engineering, Chinese Academy of Sciences studied the influence of PEG with different chain length on the bioactivity of GHA. In this work, 20kDa and 40kDa PEG were used for N-terminal mono-PEGylation of GHA The relationship of the PEG size and the pharmacodynamic (PD) behavior of GHA for the development of long-acting were discussed. The balance of PD and pharmacoknitic (PK) behaviors of the modified products were studied as well.

 The results showed that PEGylation increased the hydrodynamic volume of GHA dramatically and thus increased the half-time of plasma. Thereinto, PEG with high molecular weight 40kDa greatly increased PK behavior of GHA but shield the GHR binding site of GHA which lead to significant loss of bioactivity of the protein.The PEGylation with a PEG mass of 20kDa presented more PD behavior and maintain GHA bioactivity to the largest extent while increase the plasma half-time.

 The research group developed a method of N-terminal PEGylated of GHA, found the balance of PD and PK behaviors. The results show potential for developing long-term protein drugs. More details see the full text: http://www.sciencedirect.com/science/article/pii/S0378517313005310.