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

Pharmaceutical Research
Luca RondaStefano Bettati

Abstract

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. 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. 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. Pharmaceutical restoration of the uricolytic pathway is a viable approach for the treatment of sev...Continue Reading

References

Apr 12, 2002·Journal of Pharmaceutical Sciences·Robert E JohnsonHenry T Gaud
Feb 8, 2006·Nature Chemical Biology·Ileana RamazzinaRiccardo Percudani
Jun 15, 2006·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Przemysław SikoraMałgorzata Zajczkowska
Sep 6, 2006·Journal of Molecular Biology·Giuseppe ZanottiRodolfo Berni
Aug 19, 2007·Metabolism: Clinical and Experimental·Rosa J TorresJuan G Puig
Mar 1, 2008·International Journal of Pharmaceutics·Benjaporn TreetharnmathurotRuedeekorn Wiwattanapatapee
Jan 31, 2009·Artificial Organs·Kim D Vandegriff, Robert M Winslow
Feb 19, 2009·Biotechnology Letters·José A Rodríguez-MartínezKai Griebenow
Jun 19, 2009·Bioconjugate Chemistry·Dario CacciaAndrea Mozzarelli
Jul 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·Michael S HershfieldJohn S Sundy
Sep 9, 2010·Proceedings of the National Academy of Sciences of the United States of America·William S StevensonWarren S Alexander
Dec 4, 2010·Therapeutics and Clinical Risk Management·Mattheus K Reinders, Tim L Th A Jansen
Jan 5, 2011·Nature Reviews. Drug Discovery·Naomi SchlesingerPeter Kirkpatrick
Nov 19, 2011·Journal of Controlled Release : Official Journal of the Controlled Release Society·Gianfranco Pasut, Francesco M Veronese
Feb 9, 2012·Chemical Society Reviews·Stephan Kontos, Jeffrey A Hubbell
Dec 12, 2012·The Journal of Pharmacy and Pharmacology·Hong TianWenbing Yao
Apr 26, 2013·Biopolymers·Ilhem F HakemMichael R Bockstaller
May 16, 2013·Pharmaceutical Research·Huub SchellekensVera Brinks
Dec 18, 2013·Biological & Pharmaceutical Bulletin·Fan ZhangHai-tong Wan
Feb 18, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·David Pfister, Massimo Morbidelli
Sep 13, 2014·Journal of the American Chemical Society·Emma M Pelegri-O'DayHeather D Maynard
Nov 20, 2014·Journal of the American Chemical Society·Paul B LawrenceJoshua L Price
Apr 12, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Sung In LimInchan Kwon
Nov 9, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yuan-Ye Qiu, Li-Qin Tang
Mar 9, 2017·The Cochrane Database of Systematic Reviews·Daniel Kl CheukShau Yin Ha

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Citations

Feb 12, 2019·Journal of Inherited Metabolic Disease·Gabriella JacomelliAnnalisa Santucci
Jun 17, 2020·Biomaterials Science·Chris E CooperBrandon J Reeder

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Datasets Mentioned

BETA
GMBH

Methods Mentioned

BETA
circular dichroism
size-exclusion chromatography

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