Research on PEGylated uricase by periodate oxidation and reductive- amination

CHEN Yangjian; CHEN Xinqi; ZHENG Xiangyun; SONG Xiaoda

doi:10.11665/j.issn.1000-5048.20150318

Journal of China Pharmaceutical University > 2015 > 46(3): 364-370. > DOI: 10.11665/j.issn.1000-5048.20150318

CHEN Yangjian, CHEN Xinqi, ZHENG Xiangyun, SONG Xiaoda. Research on PEGylated uricase by periodate oxidation and reductive- amination[J]. Journal of China Pharmaceutical University, 2015, 46(3): 364-370. DOI: 10.11665/j.issn.1000-5048.20150318

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Research on PEGylated uricase by periodate oxidation and reductive- amination

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Abstract

PEGylated uricase was prepared with the N-terminal amino site-specific modification by periodate oxidation followed by reductive-amination. A monomethoxy poly(ethylene glycol)intermediate was synthesized by amidation from monomethoxy poly(ethylene glycol)amine hydrochloride 20000(mPEG₂₀₀₀₀-NH₂ ·HCl)with the relative molecular mass of 20 kD and N-(tert-butoxycarbonyl)-L-serine(Boc-Ser-OH), and then the Boc group of the intermediate was removed by trifluoroacetic acid(TFA)to produce the desired product Ser-mPEG₂₀₀₀₀. This compound could be oxidated by periodate to obtain a new poly(ethylene glycol)aldehyde derivative with high activity, which could be used to modify proteins with the N-terminal amino site-specific PEGylation after ultrafiltration, and the modification conditions to uricase by Ser-mPEG₂₀₀₀₀ were optimized. The structures of poly(ethylene glycol)intermediate and the target product were characterized by IR and ¹H NMR, and the overall yield of the target product was 72. 8%. The preliminary modification to uricase indicated that the desired product Ser-mPEG₂₀₀₀₀ could modify proteins easily and efficiently. The optimal modification conditions of uricase PEGylated by Ser-mPEG₂₀₀₀₀ were obtained as follows: the molar ratio of Ser-mPEG₂₀₀₀₀ to uricase was 2 ∶1; the pH value of solution was 5. 0; the reaction temperature was 25 °C and the reaction time was 6 h.
- poly(ethylene glycol)derivative,
- N-terminal site-specific modification,
- uricase,
- periodate oxidation,
- reductive-amination

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