Trevino Saul R, Scholtz J Martin, Pace C Nick
Department of Molecular and Cellular Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843-1114, USA.
J Pharm Sci. 2008 Oct;97(10):4155-66. doi: 10.1002/jps.21327.
High concentration protein delivery is difficult to achieve for several protein pharmaceuticals due to low solubility. In this review, we discuss different types of low protein solubility, including low in vitro solubility, which is relevant to the formulation of protein pharmaceuticals. We also discuss different methods of measuring protein solubility with an emphasis on the method of inducing amorphous precipitation using ammonium sulfate. Finally, we discuss strategies for increasing protein solubility, including site-directed mutagenesis. Evidence from solubility-changing mutations in the literature indicate that some hydrophilic residues (aspartic acid, glutamic acid, and serine) contribute significantly more favorably to protein solubility than other hydrophilic residues (asparagine, glutamine, threonine, lysine, and arginine). These findings should prove useful especially in cases where protein structure is not known. In these cases, instead of targeting hydrophobic residues that are often buried, one could target hydrophilic residues that do not contribute favorably to protein solubility and replace them with hydrophilic residues that contribute more favorably.
由于溶解度低，对于几种蛋白质药物来说，实现高浓度蛋白质递送很困难。在这篇综述中，我们讨论了不同类型的低蛋白质溶解度，包括与蛋白质药物制剂相关的低体外溶解度。我们还讨论了测量蛋白质溶解度的不同方法，重点是使用硫酸铵诱导无定形沉淀的方法。最后，我们讨论了提高蛋白质溶解度的策略，包括定点诱变。文献中溶解度改变突变的证据表明，一些亲水残基（天冬氨酸、谷氨酸和丝氨酸）对蛋白质溶解度的贡献比其他亲水残基（天冬酰胺、谷氨酰胺、苏氨酸、赖氨酸和精氨酸）更有利。这些发现尤其在蛋白质结构未知的情况下应该会很有用。在这些情况下，与其靶向通常被埋藏的疏水残基，不如靶向对蛋白质溶解度贡献不利的亲水残基，并用贡献更有利的亲水残基取代它们。
