Biopharmaceutical agents such as proteins, polysaccharides, and polynucleotides save millions of lives every year. Unfortunately, some of the benefits of biopharmaceuticals are lost because they are not stable enough to be shipped or stored without expensive precautions. While much has been written about the stabilization of biopharmaceuticals, formulations are often determined empirically and reformulation is often impossible without new, costly clinical trials. In order to improve formulations and/or make reformulation possible, it is necessary to characterize the biologically active state and to measure structural changes as the agents go from their biologically active to their biologically inactive forms. As analytical methods become available, studies of the physical and chemical processes involved in molecular destabilization mechanisms provide data for systematically formulating biopharmaceuticals on the basis of inhibiting specific destabilization pathways. We are developing methods to measure the physical processes that contribute to the biological activation and inactivation of proteins and membrane proteins such as conformational changes, aggregation, and/or macromolecular association/dissociation. For example, we have used infrared methods to quantify protein structural stability and protein binding interactions by quantifying the extent of the exchange of deuterium for hydrogen in the amide bonds of proteins. This is significant because infrared spectroscopy can be used to study protein structural stability and variation in a variety of pharmaceutically relevant environments (solutions, solids, membranes, or immobilized on surfaces). Possible projects could involve characterizing the physical processes of the destabilization mechanisms of antibodies, recombinant protein drugs, membrane proteins or amyloid beta.

 

key words

Biopharmaceutical; Formulation; Infrared spectroscopy; Monolayer structure; Protein stability; Protein structure; Protein-ligand binding; Rational drug design; Structural biology;

Citizenship:  Open to U.S. citizens

Level:  Open to Postdoctoral applicants