期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：14189-14194
DOI：10.1073/pnas.1616639113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePharmaceutical practice has transitioned away from small-molecule drugs to the use of biomolecules (peptides, proteins, and antibodies). Where formulation of small molecules focused primarily on solubility, biopharmaceuticals introduced an array of complications due to their more complex secondary and tertiary structures, contributing to concerns surrounding aggregation and denaturation over time in formulation. Here, we outline an approach using noncovalent supramolecular affinity to endow biopharmaceuticals with a polymer known to inhibit protein aggregation and improve solubility. This method stands in contrast to similar approaches to covalently graft the same polymer onto the protein, instead offering a broadly useful and modular formulation excipient that can be combined with authentic unmodified protein drugs to extend shelf life. The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host-guest interactions to endow proteins with prosthetic functionality. Specifically, a series of cucurbit[7]uril (CB[7])-PEG conjugates are shown to substantially increase the stability of three distinct protein drugs in formulation. Leveraging the known and high-affinity interaction between CB[7] and an N-terminal aromatic residue on one specific protein drug, insulin, further results in altering of its pharmacological properties in vivo by extending activity in a manner dependent on molecular weight of the attached PEG chain. Supramolecular modification of therapeutic proteins affords a noncovalent route to modify its properties, improving protein stability and activity as a formulation excipient. Furthermore, this offers a modular approach to append functionality to biopharmaceuticals by noncovalent modification with other molecules or polymers, for applications in formulation or therapy.
关键词：supramolecular chemistry ; protein engineering ; drug delivery ; protein formulation
