Mary O'Sullivan, PhD Professor
PhD, University of Newcastle upon Tyne, U.K.
Teaching areas include organic chemistry, biological organic chemistry and spectroscopy. Research interests include enzyme inhibition and the development of novel anti-parasitic agents, specifically new compounds designed to combat diseases caused by trypanosomes. Dr. O'Sullivan is the recipient of the 2009 Full-Time Faculty Teaching Award from the College of Arts and Sciences.
Dr. O’Sullivan’s research group at Canisius is working primarily on developing novel compounds that inhibit an enzyme (trypanothione reductase) found in trypanosomatids. Several trypanosomatids are parasites that cause a range of diseases including African sleeping sickness, Chagas’ disease and leishmaniasis. Many of these diseases are endemic in regions of Central and South America and Africa. For example, an estimated 18 million people in South America are currently infected with Trypanosoma cruzi and suffer from Chagas’ disease. Treatment of trypanosomatid infections is extremely difficult and often involves toxic drugs based on heavy metals such as antimony and arsenic. Additionally, there is no treatment for the chronic phases of some of these diseases, and resistance by trypanosomes to current drugs is a growing problem.
|Trypanosoma brucei and red blood cells
(courtesy of WHO/TDR/Stammers)
Trypanothione reductase (TR) is an enzyme that catalyzes the reduction of the disulfide group of trypanothione (a glutathione-spermidine conjugate) to produce dihydrotrypanothione. This dithiol is involved in several important metabolic processes in trypanosomatids and is also vital to the antioxidant defenses of these parasites. TR is a homodimeric, NADPH-dependent flavoprotein disulfide reductase, which contains a redox active disulfide and is structurally similar to human glutathione reductase however, TR is not found in mammals. Since dihydrotrypanothione is required for several vital reactions in trypanosomatids, inhibition of trypanothione reductase is a potential target for the effective chemotherapy of diseases caused by trypansomatids.
|Active site of trypanothione reductase with trypanothione in active site
(C. S. Bond, et al. Structure with Folding & Design 1999, 7, 81)
Dr. O’Sullivan’s group is developing and synthesizing new and more potent inhibitors of TR. Of particular interest are several compounds prepared by Dr. O’Sullivan’s group that contain a polyamine backbone with aromatic substituents. The inhibiting effects of these polyamine derivatives on recombinant TR from Trypanosoma cruzi are assessed by Dr. O’Sullivan’s group. For example, the spermine derivative shown is a potent competitive inhibitor of TR (with a Ki value of 0.15 µM) and showed trypanocidal activity (with IC50 values ranging from 2.2 to 5.5 µM against four Trypanosoma bruceistrains in vitro).
M. Berger, A. Bitar,* M. Waitner,* P. Rebernik, M. O’Sullivan “Polyamines and the NMDA receptor: Modifying the intrinsic activities with aromatic substituents”, Bioorganic and Medicinal Chemistry Letters, 2006, 16, 2837.
Mary C. O’Sullivan “The Battle against Trypanosomiasis and Leishmaniasis: Metal-based and Natural Product Inhibitors of Trypanothione Reductase”, Anti-Infective Agents in Medicinal Chemistry (formerly Current Medicinal Chemistry: Anti-Infective Agents), 2005, 4, 355-378.
S. Pandey, K. Fletcher, S. Baker, G. Baker, J. DeLuca,* M. Fennie,* and M. O'Sullivan "Solution Aggregation of Anti-trypanosomal N-(2-naphthylmethyl)ated Polyamines", Journal of Photochemistry and Photobiology A: Chemistry, 2004, 162, 387.
Z. Li, M.W. Fennie,* B. Ganem, M.T. Hancock, M. Kobaslija,* D. Rattendi, C.J. Bacchi, M.C. O’Sullivan “Polyamines with N-(3-phenylpropyl) Substituents are Effective Competitive Inhibitors of Trypanothione Reductase and Trypanocidal Agents”, Bioorganic and Medicinal Chemistry Letters, 2001, 11, 251.