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HIV protease is a pepsin-like aspartic protease that is vital for the maturation and life cycle of HIV. HIV protease inhibitors, including peptidomimetic or nonpeptidic compounds, are widely used in the treatment of HIV infection. Differences in the aspartic protease cleavage site of HIV-1 and HIV-2 proteases means these two proteins differ in their specificity for protein substrates and inhibitors.
|Cat. No.||Product Name / Activity|
|Highly potent HIV protease inhibitor|
|Highly potent and selective HIV-1 protease inhibitor|
|Potent HIV-1 protease inhibitor|
|HIV-1 and HIV-2 protease inhibitor|
|HIV protease inhibitor|
Human Immunodeficiency Virus (HIV) is an enveloped retrovirus with a positive sense RNA genome. There is high genetic diversity within HIV and these viruses can be split into two families. HIV-1 is more common and is further subdivided into multiple subtypes. HIV-2 is mainly confined with West Africa, although it has been identified globally.
HIV protease is a pepsin-like aspartic protease that is encoded by the viral genome, and is vital for the processing of polyproteins and maturation of viral particles. It is a 22kDa homodimer, formed from two 99 amino acid monomers, with an active site located at the interface of the monomers. Each monomer contributes a catalytic Asp25 residue to the Asp-Thr-Gly catalytic triad that is characteristic of aspartic proteases.
HIV proteases from HIV-1 and HIV-2 subfamilies show approximate 40-50% amino acid sequence homology, depending on the specific HIV strains compared. They also differ in their cleavage site sequence and specificity for protein substrates and inhibitors.
Within the viral life cycle, HIV-proteases play a dual role. Precursor proteases are responsible for catalyzing the product of mature HIV proteases through auto-processing. The mature protease is then able to hydrolyze peptide bonds within viral polyproteins Gag and Gag-Pol at 9 cleavage sites to release the protein components required for release of the mature virus.
The crystal structure of HIV-1 protease has been well studied, which has aided the rapid design and development of compounds that inhibit this enzyme. As such, the development of HIV protease inhibitors is regarded as a success story for structure-based drug design. Peptidomimetic HIV-1 protease inhibitors, such as saquinavir (Cat. No. 4418) and ritonavir (Cat. No. 5856), were the first compound developed to target HIV proteases, whereas nonpeptidic inhibitors, such as darunavir (Cat. No. 6710), were developed more recently.
Retroviral proteins have high mutation rates; this is problematic for HIV therapy as changes to a few amino acids within the HIV protease can render inhibitors inactive. There are two types of mutation that are associated with an increase in drug resistance in HIV; 'major' mutations within the activity site that prevent selective inhibitors from binding, and 'secondary' mutations in other areas of the enzyme that may affect inhibitor selectivity. An approach to counter this, is to treat HIV infection with a combination of drugs, including those for other viral protein targets such as RNA polymerases and reverse transcriptase (RNA-dependent DNA polymerase).
Figure 1: Structure of HIV-1 protease. Structure taken from Protein Data Bank, PDBID: 3SPK. Wang et al (2011) The higher barrier of darunavir and tipranavir resistance for HIV-1 protease. Biochem Biophys Res Commun 412: 737-742
Tocris offers the following scientific literature for HIV Protease to showcase our products. We invite you to request* your copy today!
*Please note that Tocris will only send literature to established scientific business / institute addresses.