Abstract
Pharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid receptor (GR), are a most effective therapy for inflammatory diseases despite the fact that chronic use causes side-effects and acquired GC resistance. The design of drugs with fewer side-effects and less potential for the development of resistance is therefore considered crucial for improved therapy. Dimerization of the GR is an integral step in glucocorticoid signaling and has been identified as a possible molecular site to target for drug development of anti-inflammatory drugs with an improved therapeutic index. Most of the current understanding regarding the role of GR dimerization in GC signaling derives for dimerization deficient mutants, although the role of ligands biased toward monomerization has also been described. Even though designing for loss of dimerization has mostly been applied for reduction of side-effect profile, designing for loss of dimerization may also be a fruitful strategy for the development of GC drugs with less potential to develop GC resistance. GC-induced resistance affects up to 30% of users and is due to a reduction in the GR functional pool. Several molecular mechanisms of GC-mediated reductions in GR pool have been described, one of which is the autologous down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Loss of GR dimerization prevents autologous down-regulation of the receptor through modulation of interactions with components of the UPS and post-translational modifications (PTMs), such as phosphorylation, which prime the GR for degradation. Rational design of conformationally biased ligands that select for a monomeric GR conformation, which increases GC sensitivity through improving GR protein stability and increasing half-life, may be a productive avenue to explore. However, potential drawbacks to this approach should be considered as well as the advantages and disadvantages in chronic vs. acute treatment regimes.
Highlights
Glucocorticoids are a cost-effective effective therapy for inflammatory and autoimmune diseases and are widely prescribed [1,2,3]
The ability of the glucocorticoid receptor (GR) monomer to repress pro-inflammatory genes activated by NFκB or AP-1, while activating genes that result in the metabolic side-effects of glucocorticoids via the dimer binding to glucocorticoid response elements (GREs) suggested that separation of the transrepression and transactivation functions of the GR could give rise to safer drugs and resulted in the development of selective GR agonists (SEGRAs) or modulators (SEGRMs), collectively referred to as SEGRAMS [16,17,18,19,20,21]
In contrast to the head-to-head binding of the DNA-binding domain (DBD) to GREs, crystal structures indicate that at a negative glucocorticoid response elements (nGREs) (Figure 1B), in the TSLP gene, which is like the canonical IR-GBS sequence: CTCC(n)0−2GGAGA [41], GR binds as two monomers orientated tail-to-tail in an everted repeat orientation on opposite sides of the DNA [42]
Summary
Reviewed by: Jan Tuckermann, University of Ulm, Germany Holger M. The design of drugs with fewer side-effects and less potential for the development of resistance is considered crucial for improved therapy. Even though designing for loss of dimerization has mostly been applied for reduction of side-effect profile, designing for loss of dimerization may be a fruitful strategy for the development of GC drugs with less potential to develop GC resistance. Several molecular mechanisms of GC-mediated reductions in GR pool have been described, one of which is the autologous down-regulation of GR density by the ubiquitin-proteasome-system (UPS). Rational design of conformationally biased ligands that select for a monomeric GR conformation, which increases GC sensitivity through improving GR protein stability and increasing half-life, may be a productive avenue to explore.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
