TRV055, a G-protein-biased Agonist, is a Gq-biased Ligand of AT1R

The angiotensin II (Ang II) receptors, AT1R and AT2R, belong to the family of G protein-coupled receptors. Angiotensin II is the ligand of AT1R and AT2R. The two receptors are important in the renin-angiotensin system: they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II. AT1R and AT2R have substrate affinity in the nanomolar range and a maximal binding capacity that varies widely among tissues. The AT1R mediates the major cardiovascular effects of angiotensin II. AT2R mRNA is abundant in fetal tissues but decreases rapidly after birth.

AT1R is an angiotensin receptor with good characteristics. AT1R effects include control of blood pressure, contraction of blood vessels, electrolyte balance, aldosterone synthesis and release from the adrenal cortex. Also, it is an important effector in controlling blood pressure and volume in the cardiovascular system. Furthermore, each receptor transmits opposing effects, with AT1R mediating vasoconstriction, proliferation, fibrosis, and inflammation. In conclusion, AT1R has become the target for cardiovascular-related diseases.

TRV055 is a potent G-protein-biased AT1R agonist.

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From: DeWire SM, Violin JD. Circ Res. 2011 Jul 8;109(2):205-16.

TRV05 is a G-quadruplex (Gq)-biased ligand of AT1R. Importantly, TRV055 is a \”gain-of-function\” ligand that has >10-fold greater allosteric coupling to Gq than Ang II. TRV055 is also more efficacious in stimulating cellular Gq-mediated signaling. However, TRV055 shows similar allosteric coupling to β-arrestin as Ang II. Thus the researchers describe TRV055 as  \”Gq-biased\”. TRV055 can selectively activate the phospholipase C β (PLCβ) pathway downstream of AT1. Therefore, TRV055 has the potential to develop Gq-biased AT1R agonists.

All in all, TRV055 is a potent agonist of AT1R and efficacious in stimulating cellular Gq-mediated signaling.

Reference:

Laura M Wingler, et al. Cell. 2019 Jan 24;176(3):468-478.e11.