Pharmacology and Chemical Probe Development of the K-26 Family of Natural Product Angiotensin-I Converting Enzyme Inhibitors

Abstract

K-26 and related (R)-AHEP containing natural products have been described as some of the most potent natural product inhibitors of human angiotensin-I converting enzyme (ACE) a physiologically important enzyme central to blood pressure regulation in mammals. Despite the pharmacological relevance of this family of natural products, structural activity relationship studies have been limited and many questions remain unanswered regarding the biosynthesis and target of this metabolite. Herein we describe the pharmacology of K-26 and other related (R)-AHEP containing natural products with both mammalian and bacterial ACE. We also apply the computational tool Rosetta in structural activity relationship studies on a set of 400 K-26 variants to identify potential variants with domain selective or potent inhibitory properties and experimentally validate the predictions. Furthermore, K-26 is developed into a solid-phase chemical probe capable of capturing human ACE with potential future applications in both target and biosynthetic enzyme identification.