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A Trivalent Enzymatic System for Uricolytic Therapy of HPRT Deficiency and Lesch-Nyhan Disease

A Trivalent Enzymatic System for Uricolytic Therapy of HPRT Deficiency and Lesch-Nyhan Disease

Authors :
Romina Corsini
Anastasia Liuzzi
Stefano Bettati
Riccardo Percudani
Riccardo Piano
Marialaura Marchetti
Luca Ronda
Source :
Pharmaceutical Research
Publication Year :
2017
Publisher :
Springer US, 2017.

Abstract

Purpose Because of the evolutionary loss of the uricolytic pathway, humans accumulate poorly soluble urate as the final product of purine catabolism. Restoration of uricolysis through enzyme therapy is a promising treatment for severe hyperuricemia caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). To this end, we studied the effect of PEG conjugation on the activity and stability of the enzymatic complement required for conversion of urate into the more soluble (S)-allantoin. Methods We produced in recombinant form three zebrafish enzymes required in the uricolytic pathway. We carried out a systematic study of the effect of PEGylation on the function and stability of the three enzymes by varying PEG length, chemistry and degree of conjugation. We assayed in vitro the uricolytic activity of the PEGylated enzymatic triad. Results We defined conditions that allow PEGylated enzymes to retain native-like enzymatic activity even after lyophilization or prolonged storage. A combination of the three enzymes in an appropriate ratio allowed efficient conversion of urate to (S)-allantoin with no accumulation of intermediate metabolites. Conclusions Pharmaceutical restoration of the uricolytic pathway is a viable approach for the treatment of severe hyperuricemia. Electronic supplementary material The online version of this article (doi:10.1007/s11095-017-2167-6) contains supplementary material, which is available to authorized users.

Details

Language :
English
ISSN :
1573904X and 07248741
Volume :
34
Issue :
7
Database :
OpenAIRE
Journal :
Pharmaceutical Research
Accession number :
edsair.doi.dedup.....3d7aba51dbfd2f16705c8c207102d0bf