biostudies-literatureUnknownGrogan AHoward Hughes Medical InstituteEdna and Fred L. Mandel, Jr. FoundationNHLBI NIH HHSNational Heart, Lung, and Blood InstituteJohn Taylor Babbit FoundationNational Cancer InstituteNCI NIH HHSThe Hartwell FoundationOrthosteric β-blockers represent the leading pharmacological intervention for managing heart diseases owing to their ability to competitively antagonize β-adrenergic receptors (βARs). However, their use is often limited by the development of adverse effects such as fatigue, hypotension, and reduced exercise capacity, due in part to the nonselective inhibition of multiple βAR subtypes. These challenges are particularly problematic in treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease characterized by lethal tachyarrhythmias directly triggered by cardiac β1AR activation. To identify small molecule allosteric modulators of the β1AR that could offer enhanced subtype specificity and robust functional antagonism of β1AR-mediated signaling, we conducted a DNA-encodedThe Journal of clinical investigatione190252https://www.ebi.ac.uk/biostudies/studies/S-EPMC12700548biostudies-literatureA positive allosteric modulator of the β1AR with antagonist activity for catecholaminergic polymorphic ventricular tachycardia.PMC12700548N/AHL056687R01 HL056687HL16037R01 HL016037P30CA014236P30 CA014236Steyaert JChen QLiu JPerelli RMKahsai AWJiang HSood DJyothidasan ALefkowitz RJShaginian AGrogan AWang JRockman HALandstrom APYou CIsrael DIAhn SfalseA positive allosteric modulator of the β1AR with antagonist activity for catecholaminergic polymorphic ventricular tachycardia.Orthosteric β-blockers represent the leading pharmacological intervention for managing heart diseases owing to their ability to competitively antagonize β-adrenergic receptors (βARs). However, their use is often limited by the development of adverse effects such as fatigue, hypotension, and reduced exercise capacity, due in part to the nonselective inhibition of multiple βAR subtypes. These challenges are particularly problematic in treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease characterized by lethal tachyarrhythmias directly triggered by cardiac β1AR activation. To identify small molecule allosteric modulators of the β1AR that could offer enhanced subtype specificity and robust functional antagonism of β1AR-mediated signaling, we conducted a DNA-encoded2025-01-01T00:00:00Z2025 Oct2026-06-06T02:01:06.582Z2026-05-24T03:12:08.124ZS-EPMC127005484110081010.1172/JCI190252