Resilience to Resistance of HIV-1 Protease Inhibitors: Profile of Darunavir

The current effectiveness of HAART in the management of HIV infection is compromised by theemergence of extensively cross-resistant strains of HIV-1, requiring a significant need for newtherapeutic agents. Due to its crucial role in viral maturation and therefore HIV-1 replication andinfectivity, the HIV-1 protease continues to be a major development target for antiretroviral therapy.However, new protease inhibitors must have higher thresholds to the development of resistance andcross-resistance. Research has demonstrated that the binding characteristics between a proteaseinhibitor and the active site of the HIV-1 protease are key factors in the development of resistance.More specifically, the way in which a protease inhibitor fits within the substrate consensus volume, or“substrate envelopeâ€?, appears to be critical. The currently available inhibitors are not only smaller thanthe native substrates, but also have a different shape. This difference in shape underlies observed patternsof resistance because primary drug-resistant mutations often arise at positions in the protease wherethe inhibitors protrude beyond the substrate envelope but are still in contact with the enzyme. Sinceall currently available protease inhibitors occupy a similar space (in spite of their structural differences)in the active site of the enzyme, the specific positions where the inhibitors protrude and contact theenzyme correspond to the locations where most mutations occur that give rise to multidrug-resistantHIV-1 strains. Detailed investigation of the structure, thermodynamics, and dynamics of the active siteof the protease enzyme is enabling the identification of new protease inhibitors that more closely fitwithin the substrate envelope and therefore decrease the risk of drug resistance developing. The featuresof darunavir, the latest FDA-approved protease inhibitor, include its high binding affinity (Kd = 4.5 × 10-12 M)for the protease active site, the presence of hydrogen bonds with the backbone, and its ability to fitclosely within the substrate envelope (or consensus volume). Darunavir is potent against both wild-typeand protease inhibitor-resistant viruses in vitro, including a broad range of over 4,000 clinical isolates.Additionally, in vitro selection studies with wild-type HIV-1 strains have shown that resistance to darunavirdevelops much more slowly and is more difficult to generate than for existing protease inhibitors.Clinical studies have shown that darunavir administered with low-dose ritonavir (darunavir/ritonavir)provides highly potent viral suppression (including significant decreases in HIV viral load in patientswith documented protease inhibitor resistance) together with favorable tolerability. In conclusion, asa result of its high binding affinity for and overall fit within the active site of HIV-1 protease, darunavirhas a higher genetic barrier to the development of resistance and better clinical efficacy againstmultidrug-resistant HIV relative to current protease inhibitors. The observed efficacy, safety and tolerabilityof darunavir in highly treatment-experienced patients makes darunavir an important new therapeuticoption for HIV-infected patients.