Abstract：
BACKGROUND: Interferon-α2b is FDA approved drug for the treatment of chronic HCV and HBV, melanoma, AIDS-related KS, carcinomas, hairy cell leukemia and chronic myelogenous leukemia. However, administration of interferon-α2b to patients takes place thrice in a week due to short in vivo circulation half-life.
OBJECTIVE: To extend the circulation half-life of IFN-α2b, it is conjugated with polyethylene glycol (PEG). However, PEGylation may results in reduction of its antiviral and antiproliferative activities but on the other side, it results in prolonged plasma half-life.
METHODS: Human interferon-α2b was PEGylated with linear 20kDa methoxypolyethlene glycol (mPEG) Propionaldehyde (IFN-Ald20K), Y-Shaped 40kDa mPEG-Propionaldehyde (IFNAld40K), linear 20-kDa mPEG-Succinimidyl Succinate (IFN-NHS20K), and Y shaped 40kDa mPEG-Succinimidyl Succinate (IFN-NHS40K). Impact of PEG size, shape and PEGylation site was studied to establish their relationship with antiprolifetaive activities and serum retention time of PEGylated IFN-α2b.
RESULTS: RP-HPLC studies showed that larger PEGs (40kDa) increased the hydrodynamic volume and increased the serum retention time while antiproliferative activity in HepG2 cell line was decreased with increase in PEGylated interferon-α2b size. Molecular docking results also dictated the same effect that increase in PEGylated interferon-α2b size results in steric shielding of the receptor-binding site on interferon-α2b. IFN-Ald20K showed highest (45%) biological activity with serum half-life 40 hours while IFN-NHS40K showed least (7%) biological activity with serum halflife 56 hours.
CONCLUSIONS: Thus, IFN-Ald40K with 12% residual activity and 62 hours of serum half-life proved to be a potent candidate for anticancer and antiviral effect with enhanced serum retention time.
OBJECTIVE: To extend the circulation half-life of IFN-α2b, it is conjugated with polyethylene glycol (PEG). However, PEGylation may results in reduction of its antiviral and antiproliferative activities but on the other side, it results in prolonged plasma half-life.
METHODS: Human interferon-α2b was PEGylated with linear 20kDa methoxypolyethlene glycol (mPEG) Propionaldehyde (IFN-Ald20K), Y-Shaped 40kDa mPEG-Propionaldehyde (IFNAld40K), linear 20-kDa mPEG-Succinimidyl Succinate (IFN-NHS20K), and Y shaped 40kDa mPEG-Succinimidyl Succinate (IFN-NHS40K). Impact of PEG size, shape and PEGylation site was studied to establish their relationship with antiprolifetaive activities and serum retention time of PEGylated IFN-α2b.
RESULTS: RP-HPLC studies showed that larger PEGs (40kDa) increased the hydrodynamic volume and increased the serum retention time while antiproliferative activity in HepG2 cell line was decreased with increase in PEGylated interferon-α2b size. Molecular docking results also dictated the same effect that increase in PEGylated interferon-α2b size results in steric shielding of the receptor-binding site on interferon-α2b. IFN-Ald20K showed highest (45%) biological activity with serum half-life 40 hours while IFN-NHS40K showed least (7%) biological activity with serum halflife 56 hours.
CONCLUSIONS: Thus, IFN-Ald40K with 12% residual activity and 62 hours of serum half-life proved to be a potent candidate for anticancer and antiviral effect with enhanced serum retention time.
摘要：
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