Ligand Bias: Increasing Specificity and Reducing Side Effects of Drug Compounds

Ligand bias is the ability of compounds to exert differential signal transduction responses on activation of a GPCR. This is a relatively new area for drug discovery and offers novel approaches to develop pharmaceuticals that have enhanced specificity and reduced side effects.

When a ligand binds to a G-protein coupled receptor, it alters the conformation of the protein, which is transduced through the plasma membrane to induce cell signaling. There are multiple ways signal transduction is mediated through GPCRs:

G-proteins to modulate second messengers such as cAMP or calcium
β-arrestins

β-arrestins are involved in regulating the duration of receptor signaling by associating with activated receptors and blocking further G-protein binding and signaling. β-arrestins subsequently form complexes with kinases such as MAPK and Erk to provide alternate signaling events.

Applications for Ligand Bias

Potential applications for ligand bias are highlighted by observations that these distinct signaling pathways can have significantly diverse effects either as a result of a medical condition, such as hypertension, or due to unforeseen consequences of drug action, such as opiates.

Angiotensin II Ligand Bias

Drug candidate TRV027, currently in Phase IIb trials for acute heart failure from Trevena Pharmaceuticals, is one such drug that uses ligand bias in GPCR signaling to tease out the positive effects from the negative effects of receptor activation.

Angiotensin II plays a central role in heart failure by regulating blood pressure, cardiac cell function and renal function. In cases of acute heart failure, angiotensin II has been shown to make the symptoms worse via second messenger signaling that results in vasoconstriction, reducing blood flow to the heart. Therefore, a drug that blocks this deleterious effect of angiotensin II has proven to show positive results for patients with acute heart failure.

In contrast, angiotensin II also promotes cardiac health and protects cardiac cells from dying through signaling via β-arrestin. Blocking this positive effect of angiotensin II activity through the β-arrestin response can make the heart condition worse. The development of drugs, such as TRV027, that specifically activate the β-arrestin pathway while simultaneously inhibiting second messenger signaling from angiotensin II type 1 receptor (AT1R) can block the negative effects of angiotensin II while promoting its positive effects.

Opioid Ligand Bias

G-proteins are not always the bad guys in signaling. For pain sensation, the body has the ability to naturally suppress pain sensation by downregulating the transmission of pain signals to the brain. Naturally occurring endorphins released by inhibitory neurons activate opioid receptors on synaptic terminals. This dampens neuronal signal transmission by reducing cAMP levels in the terminal.

Opiate drugs, such as morphine, produce pain relief by mirroring the actions of endorphins. Unfortunately, since opiate drugs are systemically applied, they also act on opioid receptors present in other parts of the body, such as the gut and lungs. The effects are significant with constipation and cramping in the gut and respiratory suppression in the lungs. These perceived negative effects are largely driven via β-arrestin signaling. Therefore, while opiates provide effective pain control, the side effects limit dosage and produce significant complications.

The next generation of opiate drugs in development are biased ligands that target the second messenger pathway and minimize β-arrestin engagement, thus reducing the negative side effects of opioid pain treatment. Oliceridine (TRV130), a Phase 3 drug for intravenous treatment for the management of moderate-to-severe acute pain, is one such drug that activates the second messenger response, and not the β-arrestin response, using biased GPCR signaling.

Assays to Measure Ligand Bias

The development of biased ligands requires tools to measure signaling via different pathways plus methods for analyzing results in order to quantify bias.

Assays for β-arrestin recruitment and signaling via cAMP modulation or calcium mobilization are needed to define compound activity in both potency and efficacy terms since bias can be presented in either pathway.
Quantifying bias between pathways that accounts for natural system bias is important. The method proposed by Dr. Terry Kenakin at the University of North Carolina achieves this by utilizing the Black and Leff operational model and normalizing compound activity to reference ligand responses.

What is clear is that biased ligand development is opening a new chapter in drug discovery by taking compound specificity a step further to address not only receptor specificity but also downstream signaling selectivity to ensure the most positive outcome for the patient with minimum side effects.