Role of the National Cancer Institute in acquired immunodeficiency syndrome-related drug discovery.

Abstract

The primary role of the Developmental Therapeutics Program of the National Cancer Institute (NCI) is to facilitate drug discovery by the extramural cancer and acquired immunodeficiency syndrome (AIDS) research communities. This role is accomplished in a variety of ways through grants programs, web-based informatics, provision of chemicals and natural product extracts, and screening services that will be described briefly in this article. Recently, the NCI has begun efforts to bring together molecular-targeted, high-throughput screening and extramural sites with chemical libraries of interest. This new initiative is designed to match emerging molecular targets and high-throughput assay technology with novel sources of chemical diversity in the extramural community. Shortly after recognition of the AIDS epidemic, the Developmental Therapeutics Program (DTP) of the NCI was charged with developing a drug-screening program that might give rise to the discovery of novel therapeutics for the treatment of human immunodeficiency virus (HIV) disease. Beginning in 1987 and continuing through 1997, a functional screen for primary antiviral treatments with the use of a cell-based assay system was in place. Details of the colorimetric-assay methodology and screening strategy have been published (1,2). This screening program supported discovery of numerous lead compounds, from both natural and synthetic sources, many of which were subsequently demonstrated to be nucleoside and non-nucleoside reverse transcriptase inhibitors. A substantial number of novel natural product agents with anti-HIV activity have been isolated, including cyanovirin, a novel gp120-binding protein derived from a cultured blue-green alga (3). Detailed information on these molecules may be found on the DTP web site (http://dtp.nci.nih. gov), which is described below in detail. Several novel molecules identified by the screen, or derivatives of screening leads, have been developed to the point of clinical trials. The nucleoside analog 3TC was submitted to the screen as a racemic mixture by IAF Biochem International, Inc. (Ville de Laval, Quebec), a Canadian pharmaceutical company, and subsequently licensed to Glaxo-Wellcome (Research Triangle Park, NC) for clinical development. This drug and Ziagen, a prodrug form of carbovir (4) also licensed by GlaxoWellcome, have been approved by the U.S. Food and Drug Administration for use in the treatment of HIV disease. PROGRAM REVIEWS