"PEGs used to modify drugs are divided into two types according to the structure: the linear type and the branched type. For example, Pegasys.RTM. (PEGylated interferon .alpha.2a injection, PEGASYS.RTM., Roche US) employs a U-shaped branched double-stranded PEG derivative, with an average molecular weight ranging from 26 KD-66 KD (U.S. Pat. No. 5,382,657--Filed
"##STR00001## wherein, R and R' are independently low molecular weight alkyl groups, n and n' are from 600 to 1500.
"Linear PEG molecule having a molecular weight of 20kD is used in NEULASTA.RTM. (pegylated granulocyte colony-stimulating factor,
"PEGs with different configurations are used, to modify proteins, resulting in products with apparently different features. Prior art literature (Monfardini C, Schiavon O, Caliceti P, et al. Bioconjugate Chem, 1995, 6 (1):62-69) reports that comparing to linear PEG, branched PEG improves the protein's pH resistance, thermal stability and resistance to protease digestion.
"Chinese Patent ZL 03801105.0 reported a new double-stranded Y-shaped PEG derivative, which has the following basic structure:
"##STR00003## wherein, Pa and Pb are the same or different hydrophilic polymers, which can be polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyacrylmorpholine or their copolymers, preferably is polyethylene glycol and its copolymers;
"j is an integer from 1 to 12;
"Ri is H, a substituted or unsubstituted C.sub.1-12 alkyl group, a substituted aryl, an aralkyl or a heteroalkyl;
"X.sub.1 and X.sub.2 are independently a linking group, wherein X.sub.1 is (CH.sub.2).sub.n, and X.sub.2 is selected from the group consisting of (CH.sub.2).sub.n, (CH.sub.2).sub.nOCO, (CH.sub.2).sub.nNHCO, and (CH.sub.2).sub.nCO; n is an integer from 1 to 10; and
"F is a terminal group selected from the group consisting of a hydroxyl group, a carboxyl group, an ester group, acyl chloride, hydrazide, maleimide, pyridine disulfide, capable of reacting with amino, hydroxyl or mercapto group of a therapeutic agent or a protein to form a covalent bond.
"When Pa and Pb are preferably PEG or its copolymer, the basic molecular structure thereof is
"The Y-shaped PEG modifies the protein on the free amino group of the protein, wherein the modification site is not fixed.
"In prior art, N-hydroxysuccinimide activation can be used to synthesize Y-shaped branched NHS-PEG which is used for modification. NHS-PEG is characterized in that it can form amide bond with the free amino group on lysine or the free terminal amino group of rhG-CSF, and the amide bond can be hydrolyzed in vivo slowly, so that the activity of rhG-CSF is restored. However, the currently used Y-shaped branched NHS-PEG generally have the defect of high activity and poor selectivity, and cannot be used to achieve directional selection of modification sites, therefore it is difficult to obtain products with modification on a single fixed-site."
Most Popular Stories
- NSA Defends Global Cellphone Tracking Legality
- Apple Paid Its Lawyers More Than $60MM to Defeat Samsung in Court
- Economic Bright Spots Not a Sure Boost for President Obama
- Starbucks Gets Grinchy; No Gingerbread Lattes for Tampa Customers
- US Consumer Borrowing Rose $18.2B in Oct.
- 2014 World Cup Official Noisemakers Quieter than Vuvuzelas
- Apple Wants Samsung to Pay $22M for Patent Dispute Legal Bills
- Dish Network Leads 2013 Top 50 Advertisers List
- Obamacare Doing Just Fine, Ky. Governor Says
- North Korea Frees 85-Year-Old Vet Merrill Newman