Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery

Slosky, Lauren M.; Caron, Marc G.; Barak, Lawrence S

doi:10.1016/j.tips.2020.12.005

Cited by 125 publications

(87 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Researchers have begun identifying on-target pathway associations between desired and unwanted affects in drug use; biased allosteric modulators (BAMs) of GPCRs, including NTS1, have been developed for the treatment of patients suffering from drug addiction and its related symptoms. 44 As this study has shown for enNTS1, allosteric fine-tuning of conformers is a well-regulated phenomenon for downstream stimulation of varying transducer molecules, and could be utilized as a targeted therapeutic. With the design of novel BAM molecules, a molecular understanding of the resulting conformational bias is required.…”

Section: Discussionmentioning

confidence: 86%

The Effect of Ligands and Transducers on the Neurotensin Receptor 1 (NTS1) Conformational Ensemble

Dixon

Inoue

Robson

et al. 2021

Preprint

View full text Add to dashboard Cite

Using a discrete, intracellular 19F-NMR probe on Neurotensin receptor 1 (NTS1) transmembrane helix (TM) 6, we aim to understand how ligands and transducers modulate the receptors structural ensemble in solution. For apo NTS1, 19F-NMR spectra reveal an ensemble of at least three states (one inactive and two active-like) in equilibrium that exchange on the ms-s timescale. Dynamic NMR experiments reveal that these substates follow a linear three-site exchange process that is both thermodynamically and kinetically remodeled by orthosteric ligands. As previously observed in other GPCRs, the full agonist is insufficient to completely stabilize the active state. Receptor coupling to b-arrestin-1 or the C-terminal helix of Gaq, which comprises >60% of the GPCR/G protein interface surface area, abolishes the inactive substate. But whereas b-arrestin-1 selects for preexisting active-like substates, the Gaq peptide induces two new substates. Both transducer molecules promote substantial line-broadening of active states suggesting contributions from additional us-ms exchange processes. Together, our study suggests i) the NTS1 allosteric activation mechanism is alternatively dominated by induced fit or conformational selection depending on the coupled transducer, and ii) the available static structures do not represent the entire conformational ensemble observed in solution.

show abstract

Section: Discussionmentioning

confidence: 86%

The Effect of Ligands and Transducers on the Neurotensin Receptor 1 (NTS1) Conformational Ensemble

Dixon

Inoue

Robson

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Taking these observations into account, almorexant and suvorexant, which displayed antagonist properties towards the Ca 2+ signaling pathway, were full agonists able to activate the SHP2-dependant apoptosis signaling pathway in cancer cells [ 47 ]. The ability of these ligands to discriminate some signaling pathways were defined as biased ligands [ 49 ]. The molecular explanation related to the ability of these antagonists to activate the ITIM/SHP2 signaling pathway in various cancers is currently unknown.…”

Section: Orexins and Digestive Cancersmentioning

confidence: 99%

Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target

et al. 2021

View full text Add to dashboard Cite

Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.

show abstract

“…These observations indicated that almorexant which blocked the intracellular calcium release induced by orexins was fully able to activate the pro-apoptotic signaling pathway in cancer cells. This type of molecule, able to discriminate various signaling pathways activated by one type of receptor, was termed biased ligand[ 42 ]. A very recent study on cryo-electron microscopy structure of OX2R active state revealed that one residue presents on the binding site play a central role in the receptor transition from the inactive to the active state[ 22 ].…”

Section: Orexins and Digestive Cancersmentioning

confidence: 99%

Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions

Couvineau¹,

Voisin²,

Nicole³

et al. 2021

WJG

View full text Add to dashboard Cite

Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.

show abstract

Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery

Cited by 125 publications

References 85 publications

The Effect of Ligands and Transducers on the Neurotensin Receptor 1 (NTS1) Conformational Ensemble

The Effect of Ligands and Transducers on the Neurotensin Receptor 1 (NTS1) Conformational Ensemble

Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target

Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions

Contact Info

Product

Resources

About