Modulating protein–protein interaction networks in protein homeostasis

Abstract

Protein-protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that target individual PPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPI networks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target's network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.

Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models

“…Thus, inhibiting the interaction of the RAGE cytoplasmic domain with DIAPH1 may reflect a superior approach by curating the effects of diverse ligands signaling through RAGE/DIAPH1. Indeed, significant advances in the development of protein-protein interaction inhibitors (PPI) in other settings bolster promise for this proposed approach (126,127).…”

The design and development of covalent protein-protein interaction inhibitors for cancer treatment

“…These connections may display a range of heterogeneities and complexities in macromolecular structures, forming protein dimers, multicomponent complexes, or long chains [4]. The interaction between protein subunits can be transient or permanent, identical or heterogeneous, and specific or nonspecific [3,5,6]. There are nearly 650,000 PPIs in humans, and this number continues to increase as more interaction networks become discovered [3,7].…”

“…There are nearly 650,000 PPIs in humans, and this number continues to increase as more interaction networks become discovered [3,7]. The function of proteins plays an essential role in the context of PPI networks [5]. For example, the PPI system connects different enzymes with their protein substrates and regulates the activity of proteins [5].…”

“…The function of proteins plays an essential role in the context of PPI networks [5]. For example, the PPI system connects different enzymes with their protein substrates and regulates the activity of proteins [5]. Twenty percent of proteins exist in network hubs and interact with at least 24 partners [8].…”

Transcription and Translation Inhibitors in Cancer Treatment

“…Transcription factors can drive oncogenesis as fusion proteins or by chromosomal translocation events (Bushweller, 2019). The DNA binding site of transcription factors with its positively charged environment is a difficult target for developing small-molecule inhibitors, and thus most of the recent efforts have been aimed for the protein-protein interaction (PPI) inhibition, such as RG-7388 (Arkin et al, 2014;Zhong et al, 2019). Transcription factors can be directly targeted by disrupting their transcription or translation, stabilizing their auto-inhibitory states, inducing covalent modifications with cysteine bridges or changing their post-translational modifications (Bushweller, 2019).…”