Allosteric Activation of a G Protein-coupled Receptor with Cell-penetrating Receptor Mimetics

Zhang, Ping; Leger, Andrew J.; Baleja, James D.; Rana, Rajashree; Corlin, Tiffany; Nguyen, Nga; Κούκος, Γεώργιος; Bohm, Andrew; Covic, Lidija; Kuliopulos, Athan

doi:10.1074/jbc.m115.636316

Cited by 35 publications

(29 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Through this approach, selective PAR1 and PAR2 agonist and antagonist pepducins have been generated [46]. Recent interrogation of the binding properties of the ICL3 PAR1 agonist pepducin, P1pal-19 revealed direct interaction with helix 8 (H8) of PAR1 [47]. In this study, activation of PAR1 by P1pal-19 involved the (D/N)PXXY motif in transmembrane-7 (TM7) and direct engagement with H8.…”

Section: Non-competitive Modulators Of Par Activitymentioning

confidence: 91%

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Cunningham

McIntosh

Bushell

et al. 2016

Biochemical Society Transactions

View full text Add to dashboard Cite

Since the identification of the proteinase-activated receptor (PAR) family as mediators of serine protease activity in the 1990s, there has been tremendous progress in the elucidation of their pathophysiological roles. The development of drugs that target PARs has been the focus of many laboratories for the potential treatment of thrombosis, cancer and other inflammatory diseases. Understanding the mechanisms of PAR activation and G protein signalling pathways evoked in response to the growing list of endogenous proteases has yielded great insight into receptor regulation at the molecular level. This has led to the development of new selective modulators of PAR activity, particularly PAR1. The mixed success of targeting PARs has been best exemplified in the context of inhibiting PAR1 as a new antiplatelet therapy. The development of the competitive PAR1 antagonist, vorapaxar (Zontivity), has clearly shown the value in targeting PAR1 in acute coronary syndrome (ACS); however the severity of associated bleeding with this drug has limited its use in the clinic. Due to the efficacy of thrombin acting via PAR1, strategies to selectively inhibit specific PAR1-mediated G protein signalling pathways or to target the second thrombin platelet receptor, PAR4, are being devised. The rationale behind these alternative approaches is to bias downstream thrombin activity via PARs to allow for inhibition of pro-thrombotic pathways but maintain other pathways that may preserve haemostatic balance and improve bleeding profiles for widespread clinical use. This review summarizes the structural determinants that regulate PARs and the modulators of PAR activity developed to date.

show abstract

Section: Non-competitive Modulators Of Par Activitymentioning

confidence: 91%

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Cunningham

McIntosh

Bushell

et al. 2016

Biochemical Society Transactions

View full text Add to dashboard Cite

show abstract

“…For ICL3-9, a Cys 265 -monobromobimane-conjugated β 2 AR showed that the pepducin does not operate through conventional receptor activation and uniquely couples G s to the receptor [5]. In assessing the mechanism of P1pal-19's ability to activate PAR1 signalling, Zhang et al [35] used a Cys 296 -monobromobimane-conjugated PAR1 to demonstrate that P1pal-19 was able to stabilize a conformation of PAR1 that may be similar to the cognate endogenous agonist, thrombin. Further, through mutagenesis studies, the authors were able to identify critical regions in PAR1 for pepducin interaction (helix 8) and efficacy ((D/N)PXXYYY motif in transmembrane 7).…”

Section: New Insight Into the Mechanism Of Actionmentioning

confidence: 98%

From biased signalling to polypharmacology: unlocking unique intracellular signalling using pepducins

Carr

Benovic

2016

Biochemical Society Transactions

View full text Add to dashboard Cite

For over a decade, pepducins have been utilized to develop unique pharmacological profiles that have been particularly challenging for traditional drug discovery methods. It is becoming increasingly clear that these cell-penetrating lipopeptides can access receptor conformations that are currently not accessible through orthosteric targeting. This review addresses the emerging concepts in the development of pepducins including the elicitation of biased signalling, pepducin polypharmacology and recent insight into their mechanism of action.

show abstract

“…The identification of the first allosteric GPCR modulators was empirical, decades before the receptor structures were elucidated, and in some cases we now understand their structural basis. Five X-ray structures of GPCR allosteric complexes can be compared (Figure 7): muscarinic acetylcholine (Family A), corticotropin releasing hormone 1 (CRF 1 , Family B), mGlu 1 (Family C), P2Y 1 receptors (Family A) and GPR40 [92,96], with bound allosteric modulators, LY2119620 (PAM) 48 , CP-376395 (NAM) 49 , FITM (NAM) 50 , BPTU (NAM) 51 and TAK-875 (PAM, allosteric partial agonist) 52 , respectively. In each case, the location, relative to the orthosteric site is different.…”

Section: New Pharmacological Dimensionsmentioning

confidence: 99%

New paradigms in GPCR drug discovery

Jacobson

2015

Biochemical Pharmacology

153

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) remain a major domain of pharmaceutical discovery. The discovery of GPCR lead compounds and their optimization are now structure-based, thanks to advances in X-ray crystallography, molecular modeling, protein engineering and biophysical techniques. In silico screening provides useful hit molecules. New pharmacological approaches to tuning the pleotropic action of GPCRs include: allosteric modulators, biased ligands, GPCR heterodimer-targeted compounds, manipulation of polypharmacology, receptor antibodies and tailoring of drug molecules to fit GPCR pharmacogenomics. Measurements of kinetics and drug efficacy are factors influencing clinical success. With the exception of inhibitors of GPCR kinases, targeting of intracellular GPCR signaling or receptor cycling for therapeutic purposes remains a futuristic concept. New assay approaches are more efficient and multidimensional: cell-based, label-free, fluorescence-based assays, and biosensors. Tailoring GPCR drugs to a patient’s genetic background is now being considered. Chemoinformatic tools can predict ADME-tox properties. New imaging technology visualizes drug action in vivo. Thus, there is reason to be optimistic that new technology for GPCR ligand discovery will help improve the current narrowing of the pharmaceutical pipeline.

show abstract

Allosteric Activation of a G Protein-coupled Receptor with Cell-penetrating Receptor Mimetics

Cited by 35 publications

References 66 publications

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

From biased signalling to polypharmacology: unlocking unique intracellular signalling using pepducins

New paradigms in GPCR drug discovery

Contact Info

Product

Resources

About