PKG drug G1

Description: PKG drug G1 is a novel electrophilic agent that activates PKG Ialpha by selectively targeting C42 of PKG Ialpha. PKG drug G1 can couple to vasodilation and blood pressure lowering by a C42 PKG Ialpha-independent mechanism. Arterial hypertension continues to be a major health burden. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. Oxidants induce an interprotein disulfide in PKG Ialpha (protein kinase G Ialpha) at C42, which is associated with its targeting and activation, resulting in vasodilation and blood pressure lowering. PKG drug G1 has the potential as novel antihypertensives with a mechanism of action that differs from current therapies. In this way, a drug that we termed G1 was identified, which targets C42 of PKG Ialpha to induce vasodilation of isolated resistance blood vessels and blood pressure lowering in a mouse model of angiotensin II-induced hypertension. In contrast, these antihypertensive effects were deficient in angiotensin II-induced hypertensive C42S PKG Ialpha knockin mice. These transgenic mice were engineered to have the reactive cysteinyl thiol replaced with a hydroxyl so that it cannot react with endogenous vasodilatory oxidants or electrophiles such as drug G1. These studies, therefore, provide validation of PKG Ialpha C42 as the target of G1, as well as proof-of-principle for a new class of antihypertensive drugs that have potential for further development for clinical use in humans.

References: Hypertension. 2017 Sep; 70(3):577-586.