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PEGylation renders carnosine resistant to hydrolysis by serum carnosinase and increases renal carnosine levels

Carnosine’s protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with diabetic kidney disease. In contrast to rodents however, carnosine is rapidly degraded by the carnosinase-1 enzyme. To overcome th...

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Main Authors: Zhang, Shiqi (Author) , Yang, Guang (Author) , Zhang, Qinqin (Author) , Fan, Yuying (Author) , Tang, Mingna (Author) , Shen, Liuhai (Author) , Zhu, Dongchun (Author) , Zhang, Guiyang (Author) , Yard, Benito A. (Author)
Format: Article (Journal)
Language:English
Published: 04 July 2024
In: Amino acids
Year: 2024, Volume: 56, Pages: 1-9
ISSN:1438-2199
DOI:10.1007/s00726-024-03405-6
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1007/s00726-024-03405-6
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Author Notes:Shiqi Zhang, Guang Yang, Qinqin Zhang, Yuying Fan, Mingna Tang, Liuhai Shen, Dongchun Zhu, Guiyang Zhang, Benito Yard
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Summary:Carnosine’s protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with diabetic kidney disease. In contrast to rodents however, carnosine is rapidly degraded by the carnosinase-1 enzyme. To overcome this hurdle, we sought to protect hydrolysis of carnosine by conjugation to Methoxypolyethylene glycol amine (mPEG-NH2). PEGylated carnosine (PEG-car) was used to study the hydrolysis of carnosine by human serum as well as to compare the pharmacokinetics of PEG-car and L-carnosine in mice after intravenous (IV) injection. While L-carnosine was rapidly hydrolyzed in human serum, PEG-car was highly resistant to hydrolysis. Addition of unconjugated PEG to carnosine or PEG-car did not influence hydrolysis of carnosine in serum. In mice PEG-car and L-carnosine exhibited similar pharmacokinetics in serum but differed in half-life time (t1/2) in kidney, with PEG-car showing a significantly higher t1/2 compared to L-carnosine. Hence, PEGylation of carnosine is an effective approach to prevent carnosine degradations and to achieve higher renal carnosine levels. However, further studies are warranted to test if the protective properties of carnosine are preserved after PEGylation.
Item Description:Gesehen am 20.12.2024
Physical Description:Online Resource
ISSN:1438-2199
DOI:10.1007/s00726-024-03405-6

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