Author(s)

Justin Kim^*, Karanveer Sadiora^*

Thomas Jefferson High School for Science and Technology, Alexandria, VA, USA.

Protein-based therapeutics (PPTs) are drugs used to treat a variety of different conditions in the human body by alleviating enzymatic deficiencies, augmenting other proteins and drugs, modulating signal pathways, and more. However, many PPTs struggle from a short half-life due to degradation caused by irreversible protein aggregation in the bloodstream. Currently, the most researched strategies for improving the efficiency and longevity of PPTs are post-translational modifications (PTMs). The goal of our research was to determine which type of PTM increases longevity the most for each of three commonly-used therapeutic proteins by comparing the docking scores (DS) and binding free energies (BFE) from protein aggregation and reception simulations. DS and BFE values were used to create a quantitative index that outputs a relative number from −1 to 1 to show reduced performance, no change, or increased performance. Results showed that methylation was the most beneficial for insulin (p < 0.1) and human growth hormone (p < 0.0001), and both phosphorylation and methylation were somewhat optimal for erythropoietin (p < 0.1 and p < 0.0001, respectively). Acetylation consistently provided the worst benefits with the most negative indices, while methylation had the most positive indices throughout. However, PTM efficacy varied between PPTs, supporting previous studies regarding how each PTM can confer different benefits based on the unique structures of recipient proteins.

Post-Translational Modification, Protein-Based Therapeutics, Therapeutic Half-Life, Protein Aggregation, Protein Reception

Kim, J. and Sadiora, K. (2024) Systematic Analysis of Post-Translational Modifications for Increased Longevity of Biotherapeutic Proteins. Computational Molecular Bioscience, 14, 125-145. doi: 10.4236/cmb.2024.143005.