HIV Protease

HIV Protease

HIV protease is responsible for processing of the gag and gag-pol polyproteins during virion maturation. The activity of this enzyme is essential for virus infectivity, rendering the protein a major therapeutic target for AIDS treatment.


HIV protease is an enzyme cleaving newly synthesized polyproteins at nine cleavage sites for the formation of mature protein components of HIV virion. The HIV protease is a dimer where each monomer is composed of 99 amino acid residues with a catalytic Asp at position 25. Due to the dispensable role in HIV replication, HIV protease has been an important target for drug therapy. HIV protease inhibitors specifically bind to the active site by mimicking the tetrahedral intermediate of its substrate. It makes infectious virions cannot be assembled. HIV protease inhibitors are also combined with nucleoside analogues to cause profound and sustained suppression of viral replication, which prolongs life in patients with HIV infection. Highly active antiretroviral therapy (HAART) is recognized as the most effective treatment method for AIDS so far. It is the combination therapy of HIV protease inhibitors, reverse transcriptase inhibitors, and/or an integrase inhibitor. The inhibitors of HIV protease contribute to the decrease of AIDS-related mortality and AIDS has gradually become a controllable and chronic disease.

Research progress

The crucial role of HIV protease in HIV replication makes it a popular target for drug design. A great number of well-described HIV protease protein structures have significantly facilitated the design of new and improved inhibitors. There are ten HIV protease inhibitors so far approved by the Food and Drug Administration (FDA), including , , , , and darunavir. They have different molecular components and different mechanisms of the function, such as blocking the active site. They can also exert the impact on circulation concentrations of other inhibitor drugs. However, most of the inhibitors unfortunately have some side effects in regular, long-term treatment. HIV protease inhibitor-induced metabolic syndromes, such as dyslipidemia, insulin-resistance, and lipodystrophy/lipoatrophy, as well as cardiovascular and cerebrovascular diseases, are the most common side effect in clinical uses. These FDA-approved HIV protease inhibitors have similar structures and binding pattern, which may cause some same side effects of the protease inhibitor-containing regimens. Nevertheless, it seems possible that side effects of HIV protease inhibitor can be avoid by optimizing their chemical structures. For example, a new modified inhibitor named GS-8374 developed by Gilead Sciences is a modification of TMC-126 (darunavir analog). It does not affect insulin-stimulated glucose uptake or peripheral glucose disposal which are the common side effects of darunavir. There is also another novel method which is based on the substrate envelope of HIV protease to design inhibitors for developing HIV protease inhibitors. Using this strategy, RO1 has been designed with higher inhibitory efficiency than current inhibitors. In order to enhance the ability of HIV protease inhibitors, the avoidance of interactions with off-target molecules need to be taken into considerations in the further development of new inhibitors. In addition to the off-target binding, the physiological concentration of drugs is another detrimental factor leading to side effects. In such case, the development of HIV protease inhibitor prodrugs could improve water solubility and bioavailability, which optimizes pharmacokinetics and decrease side effects. It has been shown that the cell absorption can be improved and the efflux can be decreased by conjugating a valine residue to the protease inhibitor through a hydrolysable ester bond. Given the significance of HIV protease in HIV infectious progress, further studies for designing new improved inhibitors with less side effects are necessary.


1.Reyskens, K & Essop,MF. HIV protease inhibitors and onset of cardiovascular diseases: A central role for oxidative stress and dysregulation of the ubiquitin–proteasome system. Biochimica et Biophysica Acta 1842, 256-268, doi: 10.1016/j.bbadis.2013.11.019 (2014).

2. Lv Z. et al. HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV AIDS 7, 95-104, doi: 10.2147/HIV.S79956 (2015).

3. Flexner C. HIV-protease inhibitors. The New England Journal of Medicine 338, 1281-1292, doi: 10.1056/NEJM199804303381808 (1998).

4. Eron, J. HIV-1 protease inhibitors. Clinical Infectious Diseases 30, 160-170, doi: 10.1086/313853 (2000).

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