TY - JOUR
T1 - Conformational stability and self-association equilibrium in biologics
AU - Clarkson, Benjamin R.
AU - Schön, Arne
AU - Freire, Ernesto
N1 - Funding Information:
The authors are supported by grants from the National Science Foundation ( MCB0641252 ) and the National Institutes of Health ( GM56550 ).
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2016
Y1 - 2016
N2 - Biologics exist in equilibrium between native, partially denatured, and denatured conformational states. The population of any of these states is dictated by their Gibbs energy and can be altered by changes in physical and solution conditions. Some conformations have a tendency to self-associate and aggregate, an undesirable phenomenon in protein therapeutics. Conformational equilibrium and self-association are linked thermodynamic functions. Given that any associative reaction is concentration dependent, conformational stability studies performed at different protein concentrations can provide early clues to future aggregation problems. This analysis can be applied to the selection of protein variants or the identification of better formulation solutions. In this review, we discuss three different aggregation situations and their manifestation in the observed conformational equilibrium of a protein.
AB - Biologics exist in equilibrium between native, partially denatured, and denatured conformational states. The population of any of these states is dictated by their Gibbs energy and can be altered by changes in physical and solution conditions. Some conformations have a tendency to self-associate and aggregate, an undesirable phenomenon in protein therapeutics. Conformational equilibrium and self-association are linked thermodynamic functions. Given that any associative reaction is concentration dependent, conformational stability studies performed at different protein concentrations can provide early clues to future aggregation problems. This analysis can be applied to the selection of protein variants or the identification of better formulation solutions. In this review, we discuss three different aggregation situations and their manifestation in the observed conformational equilibrium of a protein.
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U2 - 10.1016/j.drudis.2015.11.007
DO - 10.1016/j.drudis.2015.11.007
M3 - Review article
C2 - 26608889
AN - SCOPUS:84949238464
SN - 1359-6446
VL - 21
SP - 342
EP - 347
JO - Drug Discovery Today
JF - Drug Discovery Today
IS - 2
ER -