It is now more than 30 years since the Human Immunodeficiency Virus (HIV) became a pandemic, and now it is still a major global pathogen. Although several classes of antiretovirals are currently available for therapy, resistance and toxicity remain the biggest threats to the successful control and treatment of HIV. Therefore it is important to increase the range of targets to help reduce the chance of treatment failure. Nef serves as a pathogencity factor, and is closely associated with disease progression to Acquired ImmunoDeficiency Syndrome (AIDS) . Using structure based drug design (SBDD) methods, a range of compounds were identified to bind Nef and prevent CD4 down-modulation by Nef. Both cellular and in vitro assays were utilised to screen molecules for inhibitory activity. A set of 11 compounds were selected for the 1st generation screen. This approach identified two 'hits' with 50% inhibition of Nef function at 10 IlM. The lead molecule was selected for structural refinement, which lead to the identification of 9 analogues for use in the 2nd generation screenings. This screen identified 3 'hits' and activity against Nef function was titrated to nanomolar concentrations. Each subsequent generation utilised a re-iterative improvement/modification process, and resulted in 3 distinct compound groups, the 3rd being used to study ' differences in activity amongst similar structures.