Therapeutic Applications of Bias
Bias By Design: Biased agonism emerged as a
pharmacologic force through pre-conceived notions of how agonist
activity could be improved. These ideas emerged from consideration of
the impact of various signals on physiology and the resulting outcomes.
The first foray into this area was with the angiotensin receptor biased
agonist/antagonist TRV027. This molecule was designed to improve the
then current therapy of losartan (an angiotensin receptor blocker
designed to block angiotensin-mediated vasoconstriction) (Violin and
Lefkowitz, 2007); TRV027 provided angiotensin blockade of
vasoconstriction with β-arrestin positive cardiac effects by being a
biased agonist toward β-arrestin away from Gαq stimulation (Violin et
al, 2006; 2010; 2014). From a theoretical point of view it is difficult
to imagine a better exemplar biased molecule for the testing of this
hypothesis in therapy. There have been many more prospective ideas
presented for molecules with modified signaling profiles to improve drug
therapy- see Table 2 of Kenakin, 2019. In general these ideas center on
the emphasis of beneficial signaling pathways (eg. β-arrestin for PTH
bone building in osteoporosis, [Ferrari et al, 2005];
β-arrestin-mediated glucagon-like peptide-1 insulin secretion in
diabetes [Sonoda et al, 2008], or the elimination of negative
signaling [opioid-mediated respiratory depression and or negative
behavioral effects mediated by β-arrestin (Raehal and Bohn, 2011; Raehal
et al, 2005; Bohn et al, 2003; Urs and Caron, 2014]). There are many
more recent proposals for improved drug candidates based on the biased
concept including agonists for muscarinic receptors (Randakova and
Jakubic, 2021; McDonald et al, 2022), opioid receptors (Che et al, 2021;
Conibear et al, 2020), Ghrelin (Mende et al, 2018), Neurotensin (Krumm
et al, 2023), Glucocorticoids (Mao et al, 2023), and 5-HT2A (Pottie et
al, 2023; Allen et al, 2011). Interestingly, efforts to achieve
selectivity through allosteric modulation in studies for Alzheimer’s
disease and schizophrenia fall short of yielding the selectivity needed
without added biased signaling (in this case, induced bias through
allosteric modulation) (van der Westhuizen et al, 2021).
Currently new approaches to the active quest for biased molecules have
been developed (i.e. DNA-encoded libraries (Cai et al, 2023). At the
receptor level techniques employing molecular dynamic simulations
(Suomivuori et al, 2020), receptor structure (Cao et al, 2023; Sengmany
et al, 2020; Vuckovic et al, 2023), receptor/β-arrestin/GRK structures
(Chen and Tesmer; 2022), and combinations of techniques (eg atomic-level
molecular dynamic simulations and functional assays) have been used to
design biased molecules (El Daibani et al, 2023). Interestingly, a case
where bias has been associated with structure is the identification of
an allosteric binding site on PTH1R (and possible other members of class
B GPCRs) which mediates only receptor interaction with G proteins and
not β-arrestin (Zhao et al, 2023).
Interest in previously forbidden targets (where activation of the target
initiates negative signaling responses) has been resurrected through
considering biased signaling. An example of this is the Κ-opioid
receptor which could be involved in cognition, reward, mood and
perception. Agonists for these receptors have possible utility as
antidepressants and anxiolytics in affective disorders, drug addiction,
and psychotic disorders. However, this receptor also produces
β-arrestin-mediated disturbing hallucinations thereby precluding
therapeutic application. Analyses of biased signaling of Κ-opioid
agonists suggests that the harmful effects of Κ-opioid agonism may be
modulated through biased signaling and convert this receptor to be a
viable therapeutic candidate protein (White et al, 2014; Che et al,
2021).
A variation on seeking bias in a new molecule is to intentionally
control the intrinsic efficacy of the molecule to diminish an unwanted
signaling effects. An added bonus of this approach is that the biased
molecule will function as an antagonist of the negative signals that
would have been produced by the natural agonist. This actually is an
important part of the biased profile for the angiotensin molecule for
heart failure TRV027; specifically, while it produces β-arrestin agonism
with an EC50 of 10 nM, it also is a competitive
antagonist at the same concentration blocking natural angiotensin
mediated agonism of vasoconstriction at the same concentration (pKi=8.0:
Violin et al, 2010 ). In fact the low intrinsic efficacy of the new
biased opioid agonist TRV130 is postulated to be an important part of
this molecule’s therapeutic profile (Che et al, 2021). Specifically,
estimation of the relative efficacy of TRV130 (vs morphine) with the
operational model of agonism (Black and Leff, 1983) shows that TRV130
has 33% of the efficacy of morphine for G protein and only 15% of the
efficacy of morphine on β-arrestin (Singleton et al, 2021). Partial
agonism of opioid receptors is being pursued as a means of bias for
other molecules as well (Lutz et al, 2023). In addition, low efficacy
for β-arrestin has been identified as an important feature of new GLP-1
biased agonists such as tirzepatide (Willard et al, 2020; Yuliantie et
al, 2020; Jones; 2021).
Bias by design also may be approached through the mechanism of
allosteric agonists. Specifically, there are data to show that
allosteric agonists tend to have a different signaling bias from
standard orthosteric agonists; for example, in a series of muscarinic m2
receptor agonists a bias plot for orthosteric and allosteric agonists
producing [35S] GTP-S and ERK1/2 responses in CHO
cells shows that the conventional orthosteric agonists are generally
biased toward GTP-γ-S while the allosteric agonists are biased toward
ERK1/2 ( Gregory et al, 2010).
Bias By Cross-Screening: Another approach is through the
evaluation of biased signaling in agonist therapy in retrospect, i.e.
cross screening molecular libraries to identify exemplar selective
agonists that show preference to one pathway over another. This
identifies molecules that specifically activate certain signaling
pathways over others which then can be explored separately to identify
possible therapeutic utility. For example, a comparative screen of
adenosine A1 receptor agonists in calcium and cyclic AMP assays
demonstrates a wide dispersion of biased compounds with little
correlations (Aurelio et al, 2018). This approach plays on the natural
expectation of allosteric probe dependence yielding bias thus reversing
the question…’should an agonist program seek bias?’ into
‘…Bias will eventually seek an agonist program’.