Allosteric Modulation of GPCRs involved in Hormone Signalling - An Alternative Approach to GPCR Therapeutics

There is a growing interest in functional tuning of GPCRs by molecules that bind outside of the orthosteric sites. Allosteric action can occur from binding sites on any accessible surface of the protein and, for membrane proteins, many drug sites are embedded within the phospholipid bilayer of cellular membranes. Very recently avacopan, a C5aR antagonist that interacts within the lipid bilayer, has been approved by the FDA for treatment of anti-neutrophil Cytoplasmic autoantibody (ANCA)-associated vasculitis. However, there are challenges in developing such a drug candidates due to high levels of membrane partitioning, poor aqueous solubility, in vivo toxicity and low oral bio availability. This route provides an alternative approach to overcome the relatively tricky nature of targeting the large binding pockets required to interact with protein/peptide ligands.
With advancements in our understanding of membrane protein structures and molecular modeling. Is there a more targeted approach to drugging allosteric sites? More traditional drug development strategies need re-evaluating when considering membrane-embedded sites for highly lipophilic therapeutic molecules, including a new understanding of PK, potency, and effective free drug concentrations.
The Topic Editors welcome the submission of novel research articles highlighting strategies or examples of targeting allosteric sites on hormone receptors to elicit functional and therapeutic responses. Particular attention will be given to research into the development of allosteric molecules and platforms to address the novel lipid-receptor interface landscape.

COI: The Topic Editors are employees of the private companies stated in affiliation.