Postdoctoral Research Initiatives

Regulation of sGC function by non-heme tetrapyrrole macrocycles

Jonathan Sessler, PhD - Department of Chemistry & Biochemistry, The University of Texas at Austin
Emil Martin, PhD - Department of Integrative Biology & Pharmacoloty, Institute of Molecular Medicine, The University of Texas Health Science Center

Soluble guanylyl cyclase, the only recognized receptor for signaling molecule nitric oxide (NO), is involved in a number of important physiological processes. These processes include, but are not limited to, smooth muscle relaxation and blood pressure regulation, platelet aggregation, neurotransmission and memory. Mice with deficient sGC enzyme develop chronic high blood pressure, making this enzyme a candidate for the pharmacological therapy or prevention of hypertension. This project involves a new approach to drug discovery that combines the expertise of the Sessler group in oligopyrrole synthesis with that of the Martin laboratory in soluble guanylyl cyclase (sGC) regulation. It has two specific aims and is predicated on the hypotheses that: 1) Replacing the normal heme found at the regulatory site of sGC with vitamin B12 and other tetrapyrroles derivatives, including those shown in the figure, will regulate the activity of this all-important enzyme, and 2) various activating systems obtained in this way will act as function mimics of NO and thus potentially act as new pharmaceutical leads that, in due course, could be used to complement or replace known NO-releasing drugs. These kinds of drugs, whose mode of action is now inexorably tied to sGC, are typically venerable species as glyceryl trinitrate, isosorbide-5-mononitrate, and isosorbide dinitrate. Unfortunately, patients often develop tolerance to these well-known nitrovasodilators, which limits their use as drugs. There is thus a need for new functional mimics of the NO-releasing agents now in use. It is the goal of this project to produce just these kinds of new functional mimics.

Jonathan L. Sessler Dept. of Chemistry & Biochemistry The University of Texas at Austin Sessler Lab

Medical School Collaborator: Emil Martin, Dept. of Integrative Biology and Pharmacology and Institute of Molecular Medicine The University of Texas Health Science Center