Inhibitors of Aspartic Proteases-Acetyl Pepstatin



Acetyl pepstatin, nature products of yeast fermentation, is general inhibitors of the family of aspartic proteases with the structure of Ac-Val-Val-Sta-Ala-Sta-OH, where staine (Sta) is the rare amino acid (4S,3S)-4-amino-3-hydroxy-6-methyheptanoic acid. It is a high affinity aspartic protease inhibitor for HIV-1 protease (Ki = 20 nM at pH 4.7) and HIV-2 protease (Ki = 5 nM at pH 4.7).

Biological Activity

A number of known inhibitors of aspartic proteases (PRs) were tested for their inhibitory properties against HIV-1 PR as soon as this enzyme was first isolated. One of the first ones was pepstain A, but another statine-containing compound, acetyl pepstatin, was subsequently described as a substantially more potent inhibitor of the HIV-1 PR, and the pH dependence of the binding was also demonstrated. The inhibitory effect of acetyl pepstain was found to have an apparent Ki value of 2.0×10-8 M at optimal pH. The crystallographic structure of acetyl pepstain bound to HIV-1 protease has shown that the inhibitor is bound in two approximately symmetric orientations. Bingding is stabilized by a network of hydrogen bonding and can der Waals interaction with the protease. Acetyl pepstatin is not only found to inhibit HIV-1 protease effectively, but also HIV-2 protease and 125I-H77, a renin inhibitor, from binding to other aspartyl proteases.


The HIV-1 protease has been the most important target in the development of antiviral therapies against HIV-1 infection. Based on the presence of the single signature sequence aspartic acid-threonine-glycine, as well as some weak homology with the eukaryotic aspartic proteases such as pepsins, it was suggested that the HIV PR and other retroviral proteases might belong to the same family. The family of aspartyl proteases has been intensely studied in the past, and knowledge gained from studies of these enzymes has allowed early inferences as to the structure and function of the dimeric HIV PR. Moreover, the intensive effort over the past two decades to make inhibitors of human renin, a member of the family of aspartic proteases, has provided great impetus to design inhibitors of HIV PR. In fact, some of these renin inhibitors have turned out to be effective inhibitors of HIV PR as well, and have served as the starting point for drug design.


1. Krisztina Matú z1, János Mótyán1, et al. Inhibition of XMRV and HIV-1 proteases by pepstatin A and acetyl-pepstatin. Febs Journal, 2012, 279 (17), 3276-3286.

2. Krzysztof Appelt. Crystal structures of HIV-1 protease-inhibitor complexes. Perspectives in Drug Discovery and Design, 1993, 1, 23-48.

3. Matthew J. Todd, Ernesto Freire. The Effect of Inhibitor Binding on the Structural Stability and Cooperativity of the HIV-1 Protease. PROTEINS: Structure, Function, and Genetics, 1999, 36,147-156.

4. Yvan Boulanger, Louis Sené;cal, Gilles Sauvé. Solution Structure of the HIV Protease Inhibitor Acetyl-pepstatin as Determined by NMR and Molecular Modeling. Journal of Biomolecular Structure & Dynamics, 1997, 14 (4), 421-428.

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