New generation of medicines targeting G-protein coupled receptors (GPCRs)

Heterotrimeric G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors (1) and play a critical role in transmitting signals from outside to inside a cell.   GPCRs role in cell physiology and pathophysiology is well documented as nearly all physiological functions are dependent on GCPR signaling (1,2).

The activation of a GPCR is a crucial step by which a cell can respond to an extracellular signal.   Activation of a GPCR by an agonist leads to a conformational change in the receptor and activation of its associated G protein.   The active G protein leads to the initiation and propagation of signaling cascades resulting in cell growth, mobility, cell division, changes in gene transcription and other cellular responses. Deactivation of the receptor is a critical process as agonist bound GPCRs are specifically turned off by G protein-coupled receptor kinases (GRKs), which results in the recruitment of arrestin and receptor signal termination (3).  Because of their diversity in number and signaling effects, GPCRs are an attractive therapeutic target and represent the largest class of drug targets with over 40% of FDA approved pharmaceuticals (4).

Recent evidence from several labs has challenged the classical GPCR signaling model of agonist activation leading to a G protein dependent signaling effect (5-8). Zhai et. al demonstrated that a mutant angiotensin II type 1 receptor (AT1R) that was unable to activate its cognitive G protein had distinct downstream signaling effects from the wild-type receptor.  Others have also shown that GPCRs possess unique signaling properties based on specific GRK and arrestin binding, again independent of the G protein.  These novel GPCR signaling cascades are referred to as G protein independent GPCR signaling (9).

The therapeutic implications for these newly discovered signaling properties are numerous, as GPCRs remain the largest class of drug targets.  Historically, pharmaceutical companies performed high throughput screening analyzing compounds only for their ability to elicit a G protein dependent signal.  However as the recent research point out, receptors are able to activate multiple downstream signaling effects through both G protein dependent and independent pathways.  Thus, it is theoretically possible to design compounds targeting GPCRs that only selectively activate one part of the complex signaling pathway while deactivating another, a term called biased agonism (9).

For example, beta-blockers (BB) and angiotensin receptor blocker (ARB) are some of the first line therapies for treating patients with cardiovascular disease (CVD).  Several different BBs and ARBs exist on the market today differing in chemical structure and specificity to receptor subtype yet all work essentially by blocking endogenous agonist activation.  In addition, both of these drug classes have proven to be safe and somewhat effective in the treatment of CVD.  Yet, if drug researchers can find ways to block the maladaptive pathways associated with CVD and activate other protective pathways, there is a huge market for this type of synergistic therapy.

Life science venture capital firms have also noted the potential impact of these new classes of drugs.  Trevena Inc., a drug discovery company targeting GPCRs closed a $24 million Series A financing in March 2008 with Alta Partners, Healthcare Ventures, New Enterprise Associates and Polaris Venture Partners.  Trevena has developed a novel drug screening technology investigating the effects of biased agonists for several diseases including heart failure and pain.  Although the development of biased agonists are several years away from FDA approval, the possibility of activating specific downstream signals while blocking others opens up the possibility of a whole new class of drugs and a new set of investment opportunities.

References:

1. Premont RT, et al. (2007). Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol 69: 511-34
2. Rohrer DK, et al. (1998). G protein-coupled receptors: functional and mechanistic insights through altered gene expression. Physiol Rev 78: 35-52
3. Moore CA, et al. (2007). Regulation of receptor trafficking by GRKs and arrestins. Annu Rev Physiol 69: 451-82
4. Eglen RM, et al. (2007). Emerging concepts of guanine nucleotide-binding protein-coupled receptor (GPCR) function and implications for high throughput screening. Assay Drug Dev Technol 5: 425-51
5. Wei H, et al. (2003) Independent B-Arrestin2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2.  PNAS 100: 10782-10787
6. Wisler JW, et al. (2007) A unique mechanism of B-blocker action: Carvedilol stimulates B-arrestin signaling. PNAS 104: 16657- 16662
7. Drake MT, et al. (2008) B-arrestin biased agonism at the B2-adrenergic receptor. JBC 283: 5669-5674
8. Zidar DA, et al. (2009) Selective engagement of G protein coupled receptor kinases encodes distinct functions of biased ligands. PNAS 106: 9649-9654
9. Rajagopal K, et al. (2005) When 7 transmembrane receptors are not G protein-coupled receptors. JCI 115: 2971- 2974