Nitric oxide has been identified as a secretory product mediating diverse functions in mammalian system including regulation of blood pressure and flow, as a mediator of many of the actions of the neurotransmitter glutamate in the central nervous system, and as a cytoxic mediator of macrophages involved in killing pathogenic organisms.  Nitric oxide is synthesized by the enzyme nitric oxide synthase (NOS) that exists in three isozymic forms, commonly referred to as nNOS, eNOS, and iNOS. Under certain conditions, NO production by nNOS has been implicated in the pathogenesis of post stroke damage and hypoxiareoxygenation injuries, while NO production by  iNOS has been implicated in the tissue damage of diverse autoimmune disorders including multiple sclerosis, arthritis, diabetes and ileitis. A key to the successful prevention of toxic NO formation is the development of inhibitors of NOS that are isoform selective, cell permeable and non-toxic in vivo. Our laboratory has pioneered the development and characterization of a novel class of NOS inhibitors, the imidazole-indazole class, which include the agents 7-nitroindazole and 1-phenylimidazole.  Most recently the focus of our research has been on inhibitors that are arginine structural mimics that have been identified as precursors that are converted at the active site of NOS during catalytic turnover to suicide intermediates.  These agents have been shown to lead either to derivatization or destruction of the active site heme residue or to lead to covalent modification of the peptide chain in the catalytic domain.  These studies have been extended to examining their effectiveness as inhibitors of NO production by cells containing the nNOS and iNOS isoforms and the cellular reversibility  of their actions. 

Recent Publications
up

Cooper, G. R., Mialkowski, K., and Wolff, D. J. (2000) Cellular and Enzymatic Studies of NO-Propyl-L-arginine and S-ethyl-N-[4-trifluoromethyl)phenyl] isothiourea as Reversible, Slowly-Dissociating Inhibitors Selective for the Neuronal Nitric Oxide Synthase Isoform. Arch. Biochem. Biophys. 375, 183 - 195.

Wolff, D. J., Papoiu, A.D.P., Mialkowski, K., Richardson, C. F., Schuster, D. I., and Wilson, S. R. (2000) Inhibition of Nitric Oxide Synthase Isoforms by Tris-Malonyl-C60-Fullerene Adducts Arch. Biochem. Biophys. 378, 216 - 223.

Wolff. D. J., Papoiu, A. D. P., Mialkowski, K., Richardson, C. F., Schuster, D. I. and Wilson, S. R. (2000) Water-Soluble Derivatives of C60-Fullerene Inhibit Nitric Oxide Synthase Electrochemical Society Proceedings 2000, 215 - 225.

Wolff, D. J., Mialkowski, K., Richardson, C. F., and Wilson, S. R. (2001) C60- Fullerene Monomalonate Adducts Inactivate Selectively Neuronal Nitric Oxide Synthase Uncoupling the Formation of Reactive Oxygen Intermediates from Nitric Oxide Production. Biochemistry 40, 37 -45 (hot article of the month).

Wolff, D. J., Barbieri, C. M., Richardson, C. F., Schuster, D. I., and Wilson, S. R. (2002) Trisamine C60-fullerene Adducts Inhibit Neuronal Nitric Oxide Synthase by Acting as Highly Potent Calmodulin Antagonists Arch. Biochem. Biophys. 399, 130 - 141.

Wolff, D. J. and Marks, N. (2002) The Antithyroid Agent 6-n-Propyl-2-Thiouracil is a Mechanism-based Inactivator of the Neuronal Nitric Oxide Synthase Isoform Arch. Biochem. Biophys. 407, 83 -94.

Mei Hong, Wen Xu, Takeshi Yoshida, Kunihiko Tanaka, Donald J. Wolff, Fanfaqn Zhou, Masayori Inouye, and Guofeng You (2005) Human Organic Ion Transporter hOAT1 Forms Heterooligomers J. Biol. Chem 280, 32285 – 32290.