Degradation of Proteins Using PROTAC- A New Technology in the Biochemistry Field
Proposal
Protein contributes immensely to sustaining the life of organisms. Correct protein folding regulates cell health and survival (Wang et al., 2020). Nonetheless, most proteins are inherently susceptible to aggregation in their misfolded condition (Wang et al., 2020). Inhibiting these molecular functions of scaffold proteins and integrated proteins is a difficult objective. However, PROTAC (proteolysis-targeting chimera) innovation could be the remedy, bearing in mind it can selectively destroy target proteins (Konstantinidou et al., 2019). The current developments in PROTAC strategy involve identification of the composition of the first ternary eutectic complex, and “PROTAC ARV-110” has been subjected to clinical trials to establish its efficacy in the treatment of prostate cancer (Wang et al., 2020). The methods for protein breakdown includes a reproduction of misfolded proteins through hydrophobic tagging; making the proteins to be hijacked by E3 “ubiquitin ligase.” In this research, therefore, PROTAC will be used to mediate the degradation of NAMPT by hijacking the activity of E3 “ubiquitin ligase” by ubiquitination and degradation using proteasome.
Background
Nicotinamide adenine dinucleotide (NAD) is a substrate for various NAD-consuming enzymes that include PARPS and sirtuins, among others, as well as being a cofactor of many enzymatic reactions (Galli et al., 2020). NAD can be synthesized a new starting from the beginning from either nicotinamide, tryptophan, and nicotic acid from the diet and also nicotinamide, which is liberated from the NAD-consuming enzymes, can be used to reform NAD. However, the nicotinamide phosphoribosyltransferase (NAMPT) acts as a bottleneck in the former instance. For most of the cells that were, the salvage pathway is dominant NAMPT acts as an important controller of the NAD concentrations and, as a result, its energy metabolism. Therefore, it is not surprising that tumoral cells overexpress NAMPT and take advantage to sustain their growth and enhance tumor progression. It, therefore, becomes necessary to develop NAMPT inhibitors in these inhibitors. This research looks into how PROTAC can be designed to bind NAMPT. It uses E3 ubiquitin ligases and the target protein that is NAMPT to enable ubiquitination and subsequent degradation. Through the protein-protein interaction of E3 ubiquitin with NAMPT protein, it is achievable to degrade the same.
Aims
- Determine the distinctive merits and the core design concept of PROTAC inhibition during the process of refolding the misfolded protein state.
- Optimization of physicochemical properties of potent compounds to get cell-permeable molecules.
- Breakdown of NAMPT by misfolded protein simulator.
References
Galli, U., Colombo, G., Travelli, C., Tron, G. C., Genazzani, A. A., & Grolla, A. A. (2020). Recent advances in NAMPT inhibitors: A novel Immunotherapic strategy. Frontiers in Pharmacology, 11. https://doi.org/10.3389/fphar.2020.00656
Konstantinidou, M., Li, J., Zhang, B., Wang, Z., Shaabani, S., Ter Brake, F., & Dömling, A. (2019). PROTACs–a game-changing technology. Expert opinion on drug discovery, 14(12), 1255-1268. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008130/
Wang, Y., Jiang, X., Feng, F., Liu, W., & Sun, H. (2020). Degradation of proteins by PROTACs and other strategies. Acta Pharmaceutica Sinica B, 10(2), 207-238. https://www.sciencedirect.com/science/article/pii/S2211383519306914#bib6