IN SEARCH OF A SMALL MOLECULE CURE FOR HIV-AIDS: DEVELOPMENT OF DUAL-ACTION AGENTS CAPABLE OF SIMULTANEOUSLY ACTIVATING HIV-1 LATENCY AND PREVENTING NEW INFECTION

We hypothesized that by activating latent HIV-1 cells out of latency and simultaneously preventing new infections by the same drug we would be able to potentially find a cure for HIV-AIDS. Dual-action drugs targeting HIV latency and preventing new infections is a novel approach that has not been explored previously. We have identified HDAC as the target for latency and HIV-1 protease (HIV-1 PR) as the target for preventing new infections. Macrocyclic inhibitors of HDAC and HIV PR were identified from literature, synthesized and subsequently studied in detail. New dual inhibitors were designed after extensive NMR and computational studies. The HDAC inhibitors, however, did not show the expected activity against HDAC 3. The macrocycles were modified by changing the linker, zinc-binding group (ZBG) and the stereochemistry and tested for inhibition of HIV-1 PR and HDAC 3. These modified compounds continued to show poor HDAC 3 inhibition. A different approach was taken by using amprenavir and incorporating different linkers and ZBG to develop dual inhibitors. We developed the first dual inhibitors of HDAC 3, and HIV PR showing low micromolar inhibition. The best inhibitor was tested in cells and demonstrated the ability to activate latently infected ACH-2 cells out of latency in a concentration dependent manner. Unfortunately, the molecule could not prevent new infections in any noticeable manner. We reasoned that with better HIV PR inhibition we would be able to achieve both of our goals. The first two new inhibitors synthesized were poor HDAC 3 inhibitors and we are currently in the process of developing new inhibitors.