A variety of phosphonamidate-containing peptides were synthesised as potential inhibitors of the HIV-1 protease. These transition state analogues were designed using known sequences from HIV-1 protease substrates and incorporated a unique Phe-Pro scissile bond mimic in an attempt to achieve selectivity over the mammalian aspartic proteases. Such compounds were found to be moderate inhibitors of the HIV-1 protease possessing IC50 values in the 1-100 μM range, both in in vitro and in vivo assays. However, the phosphonamidate methyl ester analogues showed a marked ability to enter cells and this feature was highlighted in the 1:1 ratio of in vivo/ in vitro IC50 values (generally for peptidic inhibitors, this ratio is 10-10000 fold higher, indicating poor cell uptake properties). Optimisation of the methyl ester analogues was attempted by alteration of the binding residues flanking either side of the phosphonamidate moiety. However, such alterations had only a small effect on inhibitor potency and the trends observed for the more potent hydroxyl-containing inhibitors were not seen with our compounds. These results suggest hydrogen-bond donating capacity as a key requirement for potent inhibition of the HIV-1 protease, a feature which the methyl ester analogues lack. Due to the associated problems with peptidic inhibitors, the development towards two novel non-peptidic inhibitors of the HIV-1 protease was undertaken. Both cyclic inhibitors were designed to optimise the key interactions at the core of the active site of the enzyme in an attempt for selective, highly potent, low molecular weight inhibitors. Such inhibitors were designed to replace a structural water molecule in the flap region of the enzyme, whilst maintaining the key interactions with the catalytic aspartates. For this purpose cyclic compounds possessing both alcohol functionality and ring heteroatoms were synthesised. The first sulfur-containing analogue produced a moderate inhibitor of the HIV-1 protease and provided a lead compound for further development. The second seven membered ring analogue was designed on the basis of a recent literature compound and the synthesis incorporated a novel bis-ketone, derived from diethyl L-tartrate. This synthesis has yet to be completed and is currently under investigation in our group by Neil Piggot.