Effects of localized interactions and surface properties on stability of protein-based therapeutics.

ABSTRACT:

Objectives

Protein-based therapeutics garner significant attention because of exquisite specificity and limited side effects and are now being used to accomplish targeted delivery of small-molecule drugs. This review identifies and highlights individual chemical attributes and categorizes how site-specific changes affect protein stability based on published high-resolution molecular analyses.

Key findings

Because it is challenging to determine the mechanisms by which the stability of large, complex molecules is altered and data are sparse, smaller, therapeutic proteins (insulin, erythropoietin, interferons) are examined alongside antibody data. Integrating this large pool of information with the limited available studies on antibodies reveals common mechanisms by which specific alterations affect protein structure and stability.

Summary

Physical and chemical stability of therapeutic proteins and antibody drug conjugates (ADCs) is of critical importance because insufficient stability prevents molecules from making it to market. Individual moieties on/near the surface of proteins have substantial influence on structure and stability. Seemingly small, superficial modification may have far-reaching consequences on structure, conformational dynamics, and solubility of the protein, and hence physical stability of the molecule. Chemical modifications, whether spontaneous (e.g. oxidation, deamidation) or intentional, as with ADCs, may adversely impact stability by disrupting local surface properties or higher order protein structure.

SUBMITTER: Mills BJ 

PROVIDER: S-EPMC5425321 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature