Small Molecule Therapeutics for the Potential Treatment of Heart Failure
Project Abstract:
Our investigative team discovered a link between gut microbiota and cardiovascular disease CVD Wang et al Nature 2011 Specifically we observed trimethylamineNOxide TMAO an obligatory product of gut microbiota metabolism of dietary nutrients abundant in a Western diet choline lecithin carnitine is linked to CVD risks including heart failure HF in multiple patient populations Koeth et al Nature Medicine 2013 Tang et al NEJM 2013 We also showed TMAO promotes atherosclerosis thrombosis and adverse ventricular remodeling in animal studies of HF After initial proof of concept development of a nonlethal microbial choline trimethylamine TMA lyase inhibitor Wang et al Cell 2015 we more recently developed and characterized a family of nextgeneration mechanismbased suicide substrate inhibitors that potently target gut microbial production of TMA the precursor of TMAO Roberts et al 2018 Nature Medicine We have designed synthesized and tested several hundred molecules that target microbial TMA generation and many display potent inhibition nanomolar to picomolar EC50 in vitro and efficacy in murine models of disease with no observable toxicity Our next step is lead maturation and identification of a candidate with optimized in vivo efficacy and pharmacological properties to take forward on IND enabling studies
