of a hydroxyethylen scaffold, with the only exception being the central core of tipranavir, which is based on a coumarin scaffold. a very important group on the hiv protease inhibitors is a hydroxyl group on the core motif which forms a hydrogen bond with the carboxylic acid on the asp-25 and asp-25´ residues in the binding site. hydrogen bonds between the water molecule, which is linked to ile50 and ile50', and carbonyl groups of the peptidomimetic inhibitors seem to connect them with the flap regions. on the other hand, on the nonpeptidic inhibitors, there is a proton acceptor which replaces the tetracoordinated water molecule and interacts directly with the two ile50 residues on the flap of the enzyme. specific pockets in the binding site of the hiv protease, often referred to as s1, s1',s2 and s2', recognize hydrophobic amino acids on natural substrates. the potency of inhibitors bearing hydrophobic groups complementing these areas is therefore increased. some residues in the enzyme binding site are capable of forming hydrogen bonds with hydrophilic groups on the inhibitor, for example with the thf moieties on amprenavir and darunavir. since darunavir has a bis-thf moiety, instead of a single thf moiety like on amprenavir, it can form more hydrogen bonds and increase binding energy. resistance mutations that code for alterations of the conformational shape facilitate resistance of hiv to protease inhibitors. the locations of these mutations are primarily in the active site of the hiv protease enzyme as well as outside of the active site, including those at protease cleavage sites in the gag-pol polyprotein precursors. the cleavage sites have highly diverse sequences, so the protease recognizes its substrates not based on sequence but rather the conserved 3d shape the substrates share when bound at the active site. this conserved shape has been named the substrate envelope. the active site mutations have been shown to directly change the interactions of the inhibitors, and mostly occur at positions where inhibitors contact protease residues beyond the substrate envelope. the non-active site mutations are considered to affect by other mechanisms, like influencing dimer stability and conformational flexibility. over 100 single gene point mutations have been described, of which at least 26 are specific to protease inhibitors. of these, there are about 15 primary or major mutations that are significant enough to change drug activity. many mutated residues have been found in hiv-1 protease which cause drug resistance, for example leu33 changes to ile, val, or phe; val82 to ala, phe, leu, or thr; ile84 to val; and leu90 to met. different mutations affects different protease inhibitors. for instance, mutations at leu90 evidently affect saquinavir and nelfinavir while indinavir activity is affected by mutations at met46, val82, and ile84, and fosamprenavir is affected when ile50 changes to val and at ile84. a combination of mutations can render high-level drug resistance but single mutations normally do not equate with drug resistance to protease inhibitors. the mutations can be divided into primary mutations and secondary mutations. primary mutations often have only a small effect on resistance. the chemical structures of most protease inhibitors are quite similar, so it is not surprising that some primary mutations lead simultaneously to resistance to multiple protease inhibitors. cross-resistance is one of the major problems of protease inhibitor treatment. additional mutations emerging in the protease during continuous protease inhibitor therapy are commonly referred to as secondary mutations. this can lead to high-level protease inhibitor resistance. the stanford hiv rt and protease sequence database (also called the “hiv drug resistance database”) was formed in 1998 with hiv reverse transcriptase and protease sequences from persons with well-characterized antiretroviral treatment histories, and is publicly available to query resistance mutations and genotype-treatment, genotype-phenotype, and genotype-outcome correlations although the substrate envelope provides the general strategy of designing inhibitors that mimic the substrate and stay within the envelope to avoid resistance conferred by most active site mutations, there is no general strategy to tackle the problem of drug resistance, especially due to those away from the active site. researches directed towards development of new therapies to cure aids are focused on avoiding cross-resistance to drugs that are already on the market. current status in january 2018 darunavir was still the most recent hiv protease inhibitor to reach the market. in 2006, glaxosmithkline discontinued the phase ii clinical development of brecanavir, an investigational protease inhibitor for the treatment of hiv, due to insurmountable issues regarding formulation. in the summer of 2009, glaxosmithkline and concert pharmaceuticals announced their collaboration to develop and commercialise deuterium-containing medicines. one of them is ctp-518, a protease inhibitor for the treatment of hiv, expected to enter phase i clinical trials in the second half of 2009. ctp-518 is a novel hiv protease inhibitor developed by replacing certain key hydrogen atoms of atazanavir with deuterium. pre-clinical studies have demonstrated that this modification fully retains the antiviral potency but can evidently slow hepatic metabolism and thereby increase the half life and plasma trough levels. ctp-518, therefore, has the potential to be the first hiv protease inhibitor to eliminate the need to co-dose with a boosting agent, such as ritonavir.