Abstract：
:Benzyl alcohol (BA) is the most widely used antimicrobial preservative in multidose protein formulations, and has been shown to cause protein aggregation. Our previous work on a model protein cytochrome c demonstrated that this phenomenon occurs via partial unfolding. Here, we examine the validity of these results by investigating the effect of BA on a pharmaceutically relevant protein, interferon α-2a (IFNA2). IFNA2 therapeutic formulations available on the pharmaceutical market contain BA as a preservative. Isothermal aggregation kinetics and temperature scanning demonstrated that BA induced IFNA2 aggregation in a concentration-dependent manner. With increasing concentration of BA, the apparent aggregation temperature of IFNA2 linearly decreased. Denaturant melts measured using protein intrinsic fluorescence and that of the 1-anilinonaphthalene-8-sulfonic acid dye indicated that IFNA2 stability decreased with increasing BA concentration, populating a partially unfolded intermediate. Changes in nuclear magnetic resonance chemical shifts and hydrogen exchange rates identified the structural nature of this intermediate, which correlated with an aggregation "hot-spot" predicted by computational methods. These results indicate that BA induces IFNA2 aggregation by partial unfolding rather than global unfolding of the entire protein, and is consistent with our earlier conclusions from model protein studies.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Bis RL,Singh SM,Cabello-Villegas J,Mallela KMdoi
10.1002/jps.24105subject
Has Abstractpub_date
2015-02-01 00:00:00pages
407-15issue
2eissn
0022-3549issn
1520-6017pii
S0022-3549(15)30190-8journal_volume
104pub_type
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