Structure is critical to the function, stability, immunogenicity, and biocompatibility of a therapeutic molecule. There are many biophysical tools which are capable of measuring the melting temperature, size, and binding capability of proteins, peptides, and other biomolecules. These tools only tell a part of the story. Coupling individual biophysical measurements with an understanding of the structure of the biomolecule provides a much more complete understanding of the potential biotherapeutic. Even more important than the protein’s structure is the change in structure, due to modifications in formulation, culture conditions, and accelerated stability studies. Knowledge surrounding the structure, and how the structure has changed leads to a truer understanding of the biomolecule and its likelihood of succeeding in becoming a biotherapeutic.
Secondary and tertiary structure are the most critical levels of structural characterization. The secondary structure of a protein, the alpha helices, beta-sheets, disordered regions and turns, dictate its final tertiary structure and overall function.
Historically it has been challenging to analyze a protein’s structure. Many of the techniques utilized are: slow, manual, time consuming, and require conditions which are nothing like the formulation buffer or formulation concentration for the potential biotherapeutic. Due to these challenges, researchers often ask, why do I need to analyze structure? If it were straightforward to analyze higher order structure, under relevant conditions, and in a time efficient manner; everybody would want to understand the structure of their candidate drug substances and products.
Structure is the ultimate description of the biomolecule. Structure impacts stability, aggregation state, and aggregation potential. Changes in structure precede aggregation. Structure determines function. Structure completes the story when measuring size, melting temperature, aggregation, binding, and changes in intrinsic fluorescence. The FDA requires a structural assessment of all protein biologic drugs as part of the IND filing. Structure is a key quality attribute for all biologic drugs.
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