The work done in this project has been an integral part of a team effort with NCI and NIAID laboratories to develop new inhibitors of human immunodeficiency virus (HIV) that target the highly conserved nucleocapsid protein (NCp7). The Bioorganic Chemistry Section has had the responsibility to design the actual drug candidates and to carry out their synthesis and characterization. This past year we have carried out a vigorous program of synthesis of N-substituted 2-mercaptobenzamide thioesters, their derivatives and intermediates in order to improve the oral bioavailability profile as predicted for drug-like molecules and to study structure-activity relationships using in vitro assays. A panel of over 250 compounds have been examined in order to optimize the structure of candidate drugs and explore their mechanism of actiion. These studies have allowed us to design and successfully test above-type thioesters that show optimal stability toward serum enzyme-promoted hydrolysis. Many of these compounds are active against HIV-1, HIV-2 and simian immunodeficiency virus (SIV), indicating a highly conserved target. Tests have been performed showing antiviral activity against chronically and latently infected cells and infected peripheral blood lymphocytes. A carefully updated patent application (PCT) was filed on July 24, 2002 covering the thioesters and corresponding, active free thiols. Several thioesters are active in an HIV-transgenic mouse model. Preliminary trials in SIV-infected cynomolgous monkeys, treated with a selected thioester, are in progress at the University of Pittsburg primate center.
