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Mol Genet Metab. 2010 Jan;99(1):4-9. doi: 10.1016/j.ymgme.2009.09.002.

Converting an injectable protein therapeutic into an oral form: phenylalanine ammonia lyase for phenylketonuria.

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1
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, GAC 1200, La Jolla, CA 92037, USA.

Abstract

Phenylalanine ammonia lyase (PAL) has long been recognized as a potential enzyme replacement therapeutic for treatment of phenylketonuria. However, various strategies for the oral delivery of PAL have been complicated by the low intestinal pH, aggressive proteolytic digestion and circulation time in the GI tract. In this work, we report 3 strategies to address these challenges. First, we used site-directed mutagenesis of a chymotrypsin cleavage site to modestly improve protease resistance; second, we used silica sol-gel material as a matrix to demonstrate that a silica matrix can provide protection to entrapped PAL proteins against intestinal proteases, as well as a low pH of 3.5; finally, we demonstrated that PEGylation of AvPAL surface lysines can reduce the inactivation of the enzyme by trypsin.

PMID:
19793667
PMCID:
PMC2795033
DOI:
10.1016/j.ymgme.2009.09.002
[Indexed for MEDLINE]
Free PMC Article
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