Proteases: Pivot Points in Functional Proteomics

Abstract

Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

Current Status and Perspectives of Protease Inhibitors and Their Combination with Nanosized Drug Delivery Systems for Targeted Cancer Therapy

“…To develop suitable protease inhibitors successfully, the small molecule inhibitors need to be designed and tested against dedicated diseases and tissue. 70,71 In this context, transcriptomic and proteomic analyses are crucial to validate inhibitors as specific targets. 72,73 Additionally, comprehensive molecular experiments need to be performed to investigate the cross-talk between signal transduction pathways and protease activation cascades, 70,74 which will be a base for maximizing their specificity and approving their repressor potential in vivo.…”

Are Biotransformation Studies of Therapeutic Proteins Needed? Scientific Considerations and Technical Challenges

“…In addition to their involvement in protein degradation, proteases have key physiologic roles in post-translational protein processing. Specifically, they are responsible for the regulation of blood coagulation, fibrinolysis, immune response, complement activation, peptide hormone processing, DNA replication and repair, cell signaling and proliferation, and programmed cell death (Verhamme et al, 2019). Physiologic protease activity is highly regulated to protect endogenous proteins from uncontrolled degradation.…”

Waveguide-based surface-enhanced Raman spectroscopy detection of protease activity using non-natural aromatic amino acids

“…In drug development, sensitive analysis of protease activity is of crucial importance since it allows to identify protease inhibitors, which efficiently block protease activity. As almost 600 proteases have been identified in the human genome [5], there is also a clear need for a selective, sensitive and multiplexed method of measuring protease activities.…”