PEGylation is a widely-used strategy for enhancing the pharmacokinetic properties of protein drugs. The development of chemoselective side-chain modification reactions has enabled researchers to PEGylate proteins with high selectivity at specific locations. However, aside from avoiding active sites and binding interfaces, there are few guidelines for the selection of optimal PEGylation sites. Because conformational stability is intimately related to the ability of a protein to avoid proteolysis, aggregation, and immune responses, it is possible that PEGylating a protein at sites where PEG enhances conformational stability will result in PEG-protein conjugates with enhanced pharmacokinetic properties. This talk will describe our recent efforts to understand and exploit the impact of PEGylation on protein conformational stability and to develop structure-based guidelines for selecting stabilizing PEGylation sites.

PEG-based increases to protein conformational and proteolytic stability

2019 Spring National Meeting

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