Forum: Therapeutic Applications of Reactive Oxygen and Nitrogen Species in Human Disease FORUM ON THERAPEUTIC APPLICATIONS OF REACTIVE OXYGEN AND NITROGEN SPECIES IN HUMAN DISEASE CRAIG E. THOMAS* and VICTOR DARLEY-USMAR † *Lilly Development Centre S. A., Parc Scientifique de Louvain-la-Neuve, Mont-Saint-Guibert, Belgium; and † University of Alabama at Birmingham, Center for Free Radical Biology, Department of Pathology, Birmingham, AL, USA (Received 7 March 2000; Accepted 7 March 2000) Several important discoveries have led to the concept that developing antioxidants will have potential thera- peutic benefits in a host of diverse human diseases. The first of these was the discovery of an interrelated network of small molecules and enzymes that protect the cell from reactive oxygen species (ROS). The natural corol- lary of these insights was the idea that “oxidative stress” occurs if these defenses are either compromised or over- whelmed by excess production of ROS such that the pathogenesis of human disease was initiated. Correcting such an imbalance would, on the surface, appear to provide a natural route for the development of novel pharmaceutical agents. The first forays in this direction in the early 1980s were constrained by our limited un- derstanding of free radical biology at the time, but pro- vided an important impetus for the field. With the dis- covery of nitric oxide, and its complex interaction with ROS, the spectrum of molecular targets for therapeutic intervention has increased. The entry of this sometime “beneficial” free radical into the arena has prompted multiple revisions of our perspective of antioxidants and free radicals in a cellular setting and defined a new series of compounds called reactive nitrogen species (RNS). During the last decade these ideas have matured with the identification of the three critical factors absolutely essential for rational drug design. The first of these is the identification of specific molecular targets for interven- tion. The era of the generic “antioxidant” has now per- manently run its course. This is immediately evident from the articles in this forum, which detail discrete chemical series with distinct properties to be applied to the treatment of a specific human disease. For example, a compound designed to remove superoxide is likely to have minimal effects on lipid-centered peroxyl radicals. These principles are central themes in the articles as evidenced by those describing the optimization of com- pounds specifically for scavenging of lipid peroxyl rad- icals and peroxynitrite. The second key factor has been the identification of lead compounds that can be “fine- tuned” by approaches largely based upon classical me- dicinal chemistry allied with robust and specific assays for oxidant generation. These compounds have often taken a lead from nature as exemplified herein by the metalloporphrins and glutathione peroxidase mimics. In- herent in these aspects is the need to target the antioxi- dant to the site of generation. This has been difficult to achieve but some of the approaches that can be used are described in the article showing how small molecules can be targeted to mitochondria. The third factor is coupled to the development of better analytical tech- niques in the free radical field. Such technology has provided evidence for a role for different reactive species in different human pathologies, further underpinning the need for specific, target, and organ-directed molecules rather than ill-defined scavengers of ROS or RNS. In addition, it is now clear that in some cases the deficiency of a free radical species is contributing to the disease process whereas in others a surfeit is the problem. This is exemplified by the various articles on RNS in the forum. The use of both inhibitors of endogenous NO formation and small molecules capable of releasing NO in vivo are contrasted. Some therapeutic strategies involve free rad- icals as an unforeseen side effect. The articles on hemo- globin and blood substitutes illustrate this and describe means by which this can be managed. Address correspondence to: Dr. Victor Darley-Usmar, University of Alabama at Birmingham, Center For Free Radical Biology, Department of Pathology, 1670 University Boulevard, Volker Hall G019, Birming- ham, AL 35295-0019, USA; Tel: (205) 975-9686; Fax: (205) 934- 1775; E-Mail: Darley@path.uab.edu. Free Radical Biology & Medicine, Vol. 28, No. 10, pp. 1449 –1450, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0891-5849/00/$–see front matter PII S0891-5849(00)00254-9 1449