Abstract
Formulation scientists employed in the biopharmaceutical industry face the challenge of creating liquid aqueous formulations for proteins that never had evolutionary pressure to be exceptionally stable or soluble. Yet commercial products usually need a shelf life of 2 years to be economically viable. The research done in this field is dominated by physical chemists who have developed theories like preferential interaction, preferential hydration and excluded volume to explain the mechanisms for the interaction between salt, small organic molecules and proteins. This review aims to translate the research findings on protein stability and solubility produced by the physical chemists and make it accessible to formulation scientists working within the biopharmaceutical industry.
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References
Arakawa T, Tsumoto K (2003) The effects of arginine on refolding of aggregated proteins: not facilitate refolding, but suppress aggregation. Biochem Biophys Res Commun 304:148–152
Arakawa T, Ejima D, Tsumoto K, Obeyama N, Tanaka Y, Kita Y, Timasheff SN (2007) Suppression of protein interactions by arginine: a proposed mechanism of the arginine effects. Biophys Chem 127:1–8
Batchelor JD, Olteanu A, Tripathy A, Pielak GJ (2004) Impact of protein denaturants and stabilizers on water structure. J Am Chem Soc 126:1958–1961
Batra J, Xu K, Zhou H (2009) Nonadditive effects of mixed crowding on protein stability. Proteins 77:133–138
Benton LA, Smith AE, Young GB, Pielak GJ (2012) Unexpected effects of macromolecular crowding on protein stability. Biochemistry 51:9773–9775
Boncina M, Rescic J, Vlachy V (2008) Solubility of lysozyme in polyethylene glycol–electrolyte mixtures: the depletion interaction and ion-specific effects. Biophys J 95:1285–1294
Born B, Kim SJ, Ebbinghaus S, Gruebele M, Havenith M (2009) The terahertz dance of water with the proteins: the effect of protein flexibility on the dynamical hydration shell of ubiquitin. Faraday Discuss 141:161–173
Bruzdziak P, Panuszko A, Stangret J (2013) Influence of osmolytes on protein and water structure: a step to understanding the mechanism of protein stabilization. J Phys Chem B 11:11502–11508
Bye JW, Falconer RJ (2013) Thermal stability of lysozyme as a function of ion concentration: a reappraisal of the relationship between the Hofmeister series and protein stability. Protein Sci 22:1563–1570
Bye JW, Meliga SC, Ferachou D, Zeitler JA, Falconer RJ (2014) Analysis of the hydration water around bovine serum albumin using terahertz coherent synchrotron radiation. J Phys Chem A (accepted)
Cheng W, Joshi SB, He F, Brems DN, He B, Kerwin BA, Volkin DB, Middaugh CR (2012) Comparison of high-throughput biophysical methods to identify stabilizing excipients for a model IgG2 monoclonal antibody: conformational stability and kinetic aggregation. J Pharm Sci 101:1701–1720
Collins KD (1995) Sticky ions in biological systems. Proc Natl Acad Sci USA 92:5553–5557
Comez L, Lupi L, Morresi A, Paolantoni M, Sassi P (2013) More is different: experimental results on the effect of biomolecules on the dynamics of hydration water. J Phys Chem Lett 4:1188–1192
Courtenay ES, Capp MW, Anderson CF, Record MT (2000) Vapor pressure osmometry studies of osmolyte–protein interactions: implications for the action of osmoprotectants in vivo and for the interpretation of “osmotic stress” experiments in vitro. Biochemistry 39:4455–4471
Courtenay ES, Capp MW, Record MT (2001) Thermodynamics of interactions of urea and guanidinium salts with protein surface: relationship between solute effects on protein processes and changes in water-accessible surface area. Protein Sci 10:2485–2497
Ding T, Li R, Zeitler JA, Huber TL, Gladden LF, Middelberg APJ, Falconer RJ (2010) Terahertz and far-infrared spectroscopy of alanine-rich peptides with variable ellipticity. Opt Express 18:27431–27444
Ebbinghaus S, Kim SJ, Heyden M, Yu X, Heugen U, Gruebele M, Leitner DM, Havenith M (2007) An extended dynamical hydration shell around proteins. Proc Natl Acad Sci USA 104:20749–20752
Falconer RJ, Markelz AG (2012) Terahertz spectroscopic analysis of peptides and proteins. J Infrared Millim Te 33:973–988
Falconer RJ, Marangon M, van Sluyter SC, Neilson KA, Chan C, Waters EJ (2010) Thermal stability of thaumatin-like protein, chitinase and invertase isolated from Sauvignon blanc and Semillon juice, and their role in haze formation in wine. J Agric Food Chem 58:975–980
Falconer RJ, Chan C, Hughes K, Munro TP (2011) Stabilization of a monoclonal antibody during purification and formulation by addition of basic amino acid excipients. Chem Technol Biotechnol 86:942–948
He F, Hogan S, Latpov RF, Narhi LO, Razinkov VI (2010) High throughput thermostability screening of monoclonal antibody formulations. J Pharm Sci 99:1707–1720
Hofmeister F (1888) Zur lehre von der wirkung der salze. Zweite mitteilung. Arch Exp Pathol Pharmakol 24:247–260
Jezek J, Darton NJ, Derham BK, Royle N, Simpson I (2013) Biopharmaceutical formulations for pre-filled delivery devices. Expert Opin Drug Deliv 10:811–828
Kunz W, Henle J, Ninham BW (2004) ‘Zur lehre von der wirkung der salze’ (about the science of the effect of salts): Franz Hofmeister’s historical papers. Curr Opin Colloid Interface Sci 9:19–37
Lund M, Vacha R, Jungwirth P (2008) Specific ion binding to macromolecules: effects of hydrophobicity and ion pairing. Langmuir 24:3387–3391
Makhatadze GI, Privalov PL (1990a) Heat capacity of proteins II. Partial molar heat capacity of the unfolded polypeptide chain of proteins: protein unfolding effects. J Mol Biol 213:385–391
Makhatadze GI, Privalov PL (1990b) Heat capacity of proteins I. Partial molar heat capacity of individual amino acid residues in aqueous solutions: hydration effect. J Mol Biol 213:375–384
Marcus Y (2009) Effect of ions on the structure of water: structure making and breaking. Chem Rev 109:1346–1370
Mazur K, Heisler IA, Meech SR (2011) Water dynamics at protein interfaces: ultrafast optical Kerr study. J Phys Chem A 116:2678–2685
Meliga SC, Farrugia W, Ramsland PA, Falconer RJ (2013) Cold-induced precipitation of a monoclonal IgM: a negative activation enthalpy reaction. J Phys Chem B 117:490–494
Okur HI, Kherb J, Cremer PS (2013) Cations bind only weakly to amides in aqueous solutions. J Am Chem Soc 135:5062–5067
Omta AW, Kropman MF, Woutersen S, Bakker HJ (2003) Negligible effect of ions on the hydrogen bond structure in liquid water. Science 301:347–349
Record MT, Guinn E, Pegram L, Capp M (2013) Introductory lecture: interpreting and predicting Hofmeister salt ion and solute effects on biopolymer and model processes using the solute partitioning model. Faraday Discuss 160:9–44
Rembert KB, Paterova J, Heyda J, Hilty C, Jungwirth P, Cremer PS (2012) Molecular mechanisms of ion-specific effects on proteins. J Am Chem Soc 134:10039–10046
Rupley JA, Gratton E, Careri G (1983) Water and globular proteins. Trends Biochem Sci 8:18–22
Sanchez-Ruiz JM, Lopez-Lacomba JL, Cortijo M, Mateo PL (1988) Differential scanning calorimetry of the irreversible thermal denaturation of thermolysin. Biochemistry 27:1648–1652
Santoro MM, Liu Y, Khan SMA, Hou LX, Bolen DW (1992) Increased thermal stability of proteins in the presence of naturally occurring osmolytes. Biochemistry 31:5278–5283
Schlesinger AP, Wang Y, Tadeo X, Millet O, Pielak GJ (2011) Macromolecular crowding fails to fold a globular protein in cells. J Am Chem Soc 133:8082–8085
Singh LR, Poddar NK, Dar TA, Kumar R, Ahmad F (2011) Protein and DNA destabilization by osmolytes: the other side of the coin. Life Sci 88:117–125
Sterpone F, Stirnermann G, Laage D (2012) Magnitude and molecular origin of water slowdown next to a protein. J Am Chem Soc 134:4116–4119
Svergun DI, Richard S, Koch MHJ, Sayers Z, Kuprin S, Zaccai G (1998) Protein hydration in solution: experimental observation by X-ray and neutron scattering. Proc Natl Acad Sci USA 95:2267–2272
Tadeo X, Pons M, Millet O (2007) Influence of the Hofmeister anions on protein stability as studied by thermal denaturation and chemical shift perturbation. Biochemistry 46:917–923
Timasheff SN (1993) The control of protein stability and association by weak interactions with water: how do solvents affect these processes? Annu Rev Biophys Biomol Struct 22:67–97
Timasheff SN (2002) Protein hydration, thermodynamic binding, and preferential hydration. Biochemistry 41:13473–13482
Vinh NQ, Allen SJ, Plaxco KW (2011) Dielectric spectroscopy of proteins as a quantitative experimental test of computational models of their low-frequency harmonic motions. J Am Chem Soc 133:8942–8947
Vogt FG, Kord AS (2011) Development of quality-by-design analytical methods. J Pharma Sci 100:797–812
Von Hippel PH, Wong K-Y (1965) On the conformational stability of globular proteins. J Biol Chem 240:3909–3923
Xie Q, Guo T, Liu J, Zhou HM (2004) The guanidine like effects of arginine on aminoacylase and salt-induced molten globule state. Int J Biochem Cell Biol 36:296–306
Yancey PH, Clark ME, Hand SC, Bowlus RD, Somero GN (1982) Living with water stress: evolution of osmolyte systems. Science 217:1214–1222
Yu LX (2007) Pharmaceutical quality by design: product and process development, understanding and control. Pharm Res 25:781–791
Zhang Y, Cremer PS (2009) The inverse and direct Hofmeister series for lysozyme. Proc Natl Acad Sci USA 106:15249–15253
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Bye, J.W., Platts, L. & Falconer, R.J. Biopharmaceutical liquid formulation: a review of the science of protein stability and solubility in aqueous environments. Biotechnol Lett 36, 869–875 (2014). https://doi.org/10.1007/s10529-013-1445-6
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DOI: https://doi.org/10.1007/s10529-013-1445-6