PEGylation enhancement of pH stability of uricase via inhibitive tetramer dissociation

Tian, Hong; Yuan, Guo; Gao, Xiangdong; Yao, Wenbing

doi:10.1111/j.2042-7158.2012.01575.x

Cited by 26 publications

(12 citation statements)

References 30 publications

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“…Enzymatic activity was fully preserved or even increased. Increased activity of PEGylated enzymes, though apparently counterintuitive, can be rationalized, e.g., by taking into account quaternary stabilization of oligomeric proteins (43) or selective stabilization of active conformations.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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PurposeBecause 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.MethodsWe 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.ResultsWe 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.ConclusionsPharmaceutical restoration of the uricolytic pathway is a viable approach for the treatment of severe hyperuricemia.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-017-2167-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…On the other hand, unmodified proteins instantaneously denatured in 30% ethanol [20]. PEGylation also enhances protein pH and thermal stability [21,22]. …”

Section: Chemical Modificationsmentioning

confidence: 99%

Recent Developments in Protein and Peptide Parenteral Delivery Approaches

2014

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Discovery of insulin in the early 1900s initiated the research and development to improve the means of therapeutic protein delivery in patients. In the past decade, great emphasis has been placed on bringing protein and peptide therapeutics to market. Despite tremendous efforts, parenteral delivery still remains the major mode of administration for protein and peptide therapeutics. Other routes such as oral, nasal, pulmonary and buccal are considered more opportunistic rather than routine application. Improving biological half-life, stability and therapeutic efficacy is central to protein and peptide delivery. Several approaches have been tried in the past to improve protein and peptide in vitro/in vivo stability and performance. Approaches may be broadly categorized as chemical modification and colloidal delivery systems. In this review we have discussed various chemical approaches such as PEGylation, hyperglycosylation, mannosylation, and colloidal carriers including microparticles, nanoparticles, liposomes, carbon nanotubes and micelles for improving protein and peptide delivery. Recent developments on in situ thermosensitive gel-based protein and peptide delivery have also been described. This review summarizes recent developments on some currently existing approaches to improve stability, bioavailability and bioactivity of peptide and protein therapeutics following parenteral administration.

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“…But as the altered distribution of albumin in critical illnesses is due to increase in capillary leakages, 7 and as the Size of protein has always been deemed to be an important consideration in retention within the circulation, 5 therefore increasing the molecular size and the hydrodynamic radius of HSA may be a potential approach to achieve a superior volume expander that not only can prevent the interstitial edema but also can reduce the infusion frequency. Covalent attachment of poly ethylene glycol (PEG) to the protein that is known as PEGylation, in addition to its wide advantages such as increasing thermal and physical stability, protection against enzymatic degradation, and decreasing the immunogenicity, antigenicity and toxicity of protein, [8][9][10][11][12][13][14] can increase the apparent size of protein, thus increasing its half life by reducing renal filtration and altering biodistribution. 12,[15][16][17] Various factors that can affect the properties of PEGylated protein and PEGylation reaction include: the molecular weight, structure and the number of PEG chains attached to the protein; the PEGylation site on the protein; PEGylation chemistry; pH, temperature and time of reaction; protein to PEG molar ratio; and even purification methods.…”

Section: Introductionmentioning

confidence: 99%

PEGylated Human Serum Albumin: Review of PEGylation, Purification and Characterization Methods

Akbarzadehlaleh¹,

Mirzaei²,

Mashahdi-Keshtiban³

et al. 2016

Adv Pharm Bull

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PEGylation enhancement of pH stability of uricase via inhibitive tetramer dissociation

Abstract: Characterization of PEGylated uricase provides a basis for the rational design of therapeutic PEGylated proteins.

Cited by 26 publications

References 30 publications

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

Recent Developments in Protein and Peptide Parenteral Delivery Approaches

PEGylated Human Serum Albumin: Review of PEGylation, Purification and Characterization Methods

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