December 1, 2012 Categories AG Scientific Blog, AG Scientific Products, Inhibitors


Here are 7 must know bestatin applications. Bestatin, also known as Ubenimex, is a competitive protease inhibitor. It is an inhibitor of aminopeptidase B, leukotriene A4 hydrolase, aminopeptidase N. It is being studied for use in the treatment of acute myelocytic leukemia.

1. Antimalarial Synergy between Bestatin and Endoprotease Inhibitors.

The pathway of hemoglobin degradation by erythrocytic stages of the human malarial parasite Plasmodium falciparum involves initial cleavages of globin chains, catalyzed by several endoproteases, followed by liberation of amino acids from the resulting peptides, probably by aminopeptidases. This pathway is considered a promising chemotherapeutic target, especially in view of the antimalarial synergy observed between inhibitors of aspartyl and cysteine endoproteases. The synergies observed were consistent with a combined role of endoproteases and aminopeptidases in hemoglobin catabolism in this organism. As synergies between antimicrobial agents are often inferred without proper statistical analysis, the model used may be widely applied in studies of antimicrobial drug interactions.

b-1075-bestatin_3d_structure for bestatin applications blog

Fig 1. The chemical structure of Bestatin.

2. Hinderance of HIV infection.

Bestatin, an inhibitor of leucine aminopeptidase (LAPase), significantly decreased HIV infection as reflected by a reduced number of positive immunofluorescent cells, p24 levels, reverse transcriptase activity and the number of proviral copies found in Bestatin-treated cells. Cellular and extracellular LAPase activity in infected cells was higher than the LAPase activity found in uninfected cells. However, cellular and extracellular LAPase activity as well as total protein kinase C activity was lower in Bestatin-treated cells. Conversely, the incubation of human lymphocytic HUT78 cells with LAPase promotes HIV infectivity. The possible role of LAPase in the pathophysiology of HIV was assessed by determining LAPase serum levels in HIV infected patients. LAPase activity levels were three orders of magnitude greater in sera obtained from HIV patients than those detected in sera of uninfected individuals. Although Bestatin reduced HIV infection, a moderate decrease in the reverse transcriptase activity of chronically-infected H9 human T-lymphocytic cells was observed. Based on the higher levels of LAPase present in the serum of HIV patients and on the combined inhibitory effect of Bestatin on LAPase and on protein kinase C activities, we suggest that LAPase may play an important role in the early events of HIV infection such as viral entry.

3. Effect of Bestatin on alcohol intake.

Bestatin is an aminopeptidase and enkephalinase inhibitor that elevates the levels of angiotensin II and angiotensin III. Although it has been used for years in the treatment of various forms of cancer, its application as an antialcohol drug has not been explored, despite its ability to stimulate angiotensin activity. The present study assesses the ability of bestatin to reduce chronic alcohol consumption in the genetically selected high alcohol-consuming P rats. Two groups of P rats were given 24-hr access to food, water, and 10% (v/v) alcohol. After a baseline period, half the rats received the saline vehicle and the other half ascending doses of bestatin. Each dose was administered for a minimum of 7 days. Bestatin had little effect on water intake or weight gain, but did produce a dose-dependent reduction in alcohol intake that averaged 33% and was sustained over the course of the 1-month period of administration. Years of experience with bestatin have shown it to be safe and free of major side effects. The present findings suggest that bestatin (Ubenimex) might also be useful in the treatment of alcohol abuse in humans.

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4. A potent APN inhibitor.

Bestatin, a small molecular weight dipeptide, is a potent inhibitor of various aminopeptidases as well as LTA4 hydrolase. Various physiological functions of Bestatin have been identified, viz.: (1) an immunomodifier for enhancing the proliferation of normal human bone marrow granulocyte– macrophage progenitor cells to form CFU-GM colonies; Bestatin exerts a direct stimulating effect on lymphocytes via its fixation on the cell surface and an indirect effect on monocytes via aminopeptidase B inhibition of tuftsin catabolism; (2) an immunorestorator and curative or preventive agent for spontaneous tumor; Bestatin alone or its combination with chemicals can prolongate the disease-free interval and survival period in adult acute or chronic leukemia, therefore, it was primarily marketed in 1987 in Japan as an anticancer drug and servers as the only marketed inhibitor of Aminopeptidase N (APN/CD13) to cure leukemia to date; (3) a pan-hematopoietic stimulator and restorator; Bestatin promotes granulocytopoiesis and thrombocytopoiesis in vitro and restores them in myelo-hypoplastic men; (4) an inhibitor of several natural opioid peptides. Based on the knowledge that APN can cleave several bioactive neuropeptides such as Met-enkaphalins, Leu-enkaphalins, β-Endorphin, and so on, the anti-aminopeptidase action of Bestatin also allows it to protect endopeptides against their catabolism, exhibiting analgesic activity.

5. Immunotherapy with bestatin for acute nonlymphocytic leukemia in adults.

In a cooperative randomized control study of immunotherapy with bestatin in combination with chemotherapy in adults with acute nonlymphocytic leukemia (ANLL), 101 patients (48 in the bestatin group and 53 in the control group) out of 115 patients registered were evaluated as eligible. The bestatin group achieved a statistically significant prolongation of survival compared with the control group in overall ANLL and acute myelogenous leukemia. In the analysis of patient age, the bestatin group achieved a statistically significant prolongation of both the remission duration and survival in patients aged 50 to 65 years, while the differences were not significant in the 15 to 49 age group. The bestatin group tended to achieve a higher rate of reinduction of remission in patients who had recurrence of leukemia. Side effects developed in only 5 (9.6%) of 52 patients treated with bestatin. None of these side effects were particularly serious in nature. It is concluded that bestatin is useful for prolongation of survival of adult patients with ANLL, making for a longer remission duration especially in elderly patients and with few side effects.

6. Provides a Chemical Genetics Approach to Dissect Jasmonate Signaling in Arabidopsis.

Bestatin, a potent inhibitor of some aminopeptidases, was shown previously to be a powerful inducer of wound-response genes in tomato (Lycopersicon esculentum). First, bestatin specifically activates the expression of JA- inducible genes in tomato and Arabidopsis (Arabidopsis thaliana). Second, the induction of JA-responsive genes by bestatin requires the COI1- dependent JA-signaling pathway, but does not depend strictly on JA biosynthesis. Third, microarray analysis using Arabidopsis whole-genome chip demonstrates that the gene expression profile of bestatin-treated plants is similar to that of JA-treated plants. Fourth, bestatin promotes a series of JA-related developmental phenotypes. Taken together, the unique action mode of bestatin in regulating JA-signaled processes leads us to the hypothesis that bestatin exerts its effects through the modulation of some key regulators in JA signaling. We have employed bestatin as an experimental tool to dissect JA signaling through a chemical genetic screening, which yielded a collection of Arabidopsis bestatin-resistant (ber) mutants that are insensitive to the inhibitory effects of bestatin on root elongation. Further characterization efforts demonstrate that some ber mutants are defective in various JA-induced responses, which allowed us to classify the ber mutants into three phenotypic groups: JA-insensitive ber mutants, JA-hypersensitive ber mutants, and mutants insensitive to bestatin but showing normal response to JA. Genetic and phenotypic analyses of the ber mutants with altered JA responses indicate that we have identified several novel loci involved in JA signaling.

7. Up-and down-regulation of CD13/aminopeptidase N.

Ubenimex (Bestatin), a low-molecular-mass dipeptide, has been demonstrated to have anti-tumor activities and immunomodulating activities. We here report cell growth inhibition and phenotypic changes of HL-60 and HL-60R cell lines induced by Bestatin treatment. Bestatin (0.1 microg/ml) showed remarkable cell growth inhibition against HL-60 cells, whereas it was ineffective for HL 60R cells. Bestatin also showed growth inhibition in the concentration of 1 microg/ml against HL-60R cells which are resistant to differentiation induction by DMSO and TPA. In both cell types, the effect of growth inhibition by Bestatin treatment was dose dependent. With HL-60 cells, the upregulation of CD13/aminopeptidase N was found after 1 hr, however, the downregulation was observed after 3 hrs incubation with Bestatin. On the other hand, the downregulation of CD15 and CD33 was observed after both one and 3 hrs incubation. Similarly, in HL-60R cells, the upregulation of CD13/aminopeptidase N was found temporarily (1hr), and then CD13 downregulation was observed after 3 hrs incubation with Bestatin. No notable change was observed for expression of other myeloid- related antigens, e.g. CD14 (My4, LeuM3), CD11b (OKM1), and CD34 (My10). On the basis of these observations of in vitro activity, Bestatin may also be an effective anti-leukemic agent in vivo.

1. Analysis of Antimalarial Synergy between Bestatin and Endoprotease Inhibitors Using Statistical Response-Surface Modelling. Clare S. Gavigan, Stella G. Machado, et al.
2. Bestatin-mediated inhibition of leucine aminopeptidase may hinder HIV infection Gabriel Pulido-Cejudoa, Brian Conwayc, Pierre Proulxb, et al.
3.Effect of bestatin, an aminopeptidase inhibitor, on alcohol intake in alcohol- preferring P rats. Szczepanska R, et al.
4. The analgesic activity of Bestatin as a potent APN inhibitor. Mei-Rong Jia, Tao Wei and Wen-Fang Xu.
5. Immunotherapy with bestatin for acute nonlymphocytic leukemia in adults6. SK 934. Analogs of Actinonin as Antitumor Compounds. Kazuo Ota, Soji Kurita, et al.
6. Bestatin, an Inhibitor of Aminopeptidases, Provides a Chemical Genetics Approach to Dissect Jasmonate Signaling in Arabidopsis. Wenguang Zheng, Qingzhe Zhai, et al.
7. Effect of ubenimex (Bestatin) on the cell growth and phenotype of HL-60 and HL-60R cell lines: up-and down-regulation of CD13/aminopeptidase N. Imamura N, Kimura A.
8. Wikipedia.


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