Key result
TP1 accelerates systolic blood pressure reduction by ~6 mmHg and blocks pathogenic AT1R autoantibody binding.
Why the study?
In many autoimmune diseases, chronic AT1R activation is driven by pathogenic autoantibody binding to an extracellular allosteric site. However, no allosteric AT1R inhibitors are currently available to mechanistically block these autoantibodies while preserving the orthosteric hormonal functions of AngII.
Does the novel negative allosteric modulator TP1 selectively inhibit AT1R signaling, attenuate AngII-induced hypertension, and block pathogenic autoantibody binding in preclinical models and patient sera?
Does the novel negative allosteric modulator TP1 selectively inhibit AT1R signaling, attenuate AngII-induced hypertension, and block pathogenic autoantibody binding in preclinical models and patient sera?
This preclinical study establishes TP1 as a first-in-class AT1R-selective negative allosteric modulator that attenuates AngII-induced hypertension and blocks pathogenic autoantibody binding from preeclampsia and dilated cardiomyopathy patients, offering a potential therapeutic approach where standard ARBs are contraindicated.
TP1 offers proof-of-concept for allosteric AT1R modulation; hypothesis-generating for preeclampsia and DCM, with clinical translation untested.
A major therapeutic strategy for managing cardiovascular and renal diseases is the use of angiotensin receptor blockers (ARBs). These drugs block both pathogenic and physiological signaling by the angiotensin II type 1 receptor (AT1R) by preventing angiotensin II (AngII) binding to orthosteric pocket in transmembrane portion of AT1R. However, in many autoimmune diseases, AT1R activation is chronically driven by pathogenic autoantibody binding to a distinct extracellular surface located allosteric site. Currently, there are no allosteric inhibitors of AT1R available to mechanistically prevent the autoantibodies and preserve the orthosteric hormonal functions of AngII. Here, we report the structure-guided hit-to-lead optimization of TP1, a first-in-class AT1R allosteric chemotype and negative allosteric modulator (NAM) with improved potency and drug-like properties. Computational docking and site-directed mutagenesis identified a TP1 binding mode that is distinct from the orthosteric-site binding of ARBs and AngII. Synthetically pure TP1 significantly reduced the capacity of AT1R to bind AngII without affecting AngII binding to AT2R, demonstrating an AT1R selective effect. TP1 reduced AngII-induced calcium signaling and migration in AT1R-expressing cells, arterial contraction, and increases in blood pressure in AngII-infused mice, demonstrating its activity as a NAM. Crucially, TP1 blocked binding of pathogenic autoantibodies to AT1R-expressing cells from the serum of patients with preeclampsia and dilated cardiomyopathy, a function distinct from ARBs. Together, these findings establish TP1 as a proof-of-concept, AT1R-selective NAM chemotype with therapeutic potential for AT1R autoantibody-driven conditions such as preeclampsia, where ARBs are strictly contraindicated. Developing AT1R-targeted NAM antihypertensive drugs may offer therapeutic advantages over ARBs and expand the pharmacological toolkit for this important CVD receptor.
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Singh et al. (2026) studied Preeclampsia, dilated cardiomyopathy, and AngII-induced hypertension (n=127). TP1 (AT1R-selective negative allosteric modulator) vs. AngII alone, vehicle (physiological salt solution), or AngII plus Olmesartan was evaluated on Decline in systolic blood pressure (SBP) from peak response in AngII-infused mice (MD 6.09 mmHg, 95% CI 0.67-11.50, p=0.0246). TP1 significantly accelerated systolic blood pressure reduction in AngII-infused mice (MD 6.09 mmHg, p=0.0246) and blocked AT1R autoantibody binding in preeclampsia (IC50 1.1 μM) and DCM (IC50 0.85 μM) sera.
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