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Purity: ≥98%
Pepstatin A (NSC-272671; NSC272671), a pentapeptide, is a potent and selective aspartic protease inhibitor which also inhibits HIV replication. Pepstatin A was originally isolated from the microbe. For the enzymes hemoglobin-pepsin, hemoglobin-proctase, casein-pepsin, casein-proctase, casein-acid protease, and hemoglobin-acid protease, respectively, its IC50 values are 4.5 nM, 6.2 nM, 150 nM, 290 nM, 520 nM, and 260 nM. At weak acid pH values, pepstatinA, a highly potent renin inhibitor, inhibited both human and porcine renin with IC50 values of 15 μM and 0.32, respectively. For aspartic proteinases like pepsin, cathepsins D and E, pepstatin A effectively inhibits them. Pepstatin A appears to have no harmful effects on HIV-infected cells, but it does block a portion of the intracellular processing of the HIV gag protein in H9 cells that have the virus. By preventing ERK signaling and reducing NFATc1 expression, pepstatin A also prevents osteoclast differentiation.
| Targets |
Hemoglobin-pepsin (IC50 = 4.5 nM); Hemoglobin-proctase (IC50 = 6.2 nM); Casein-pepsin (IC50 = 150 nM); Hemoglobin-acid protease (IC50 = 260 nM); Casein-proctase (IC50 = 290 nM); Casein-acid protease (IC50 = 520 nM)
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| ln Vitro |
Pepstatin A shows effectively inhibits aspartic proteinases, including cathepsins D and E and pepsin. Pepstatin A appears to have no harmful effects on HIV-infected cells, but it does block a portion of the intracellular processing of the HIV gag protein in H9 cells that have the virus.[1]
Pepstatin A laos inhibits NFATc1 expression and ERK signaling, which prevents osteoclasts from differentiating.[2] |
| ln Vivo |
Pepstatin A has a very low toxicity, with LD50s of >2000 mg/kg for all species when taken orally, and LD50s of 1090 mg/kg, 875 mg/kg, 820 mg/kg, and 450 mg/kg for mice, rats, rabbits, and dogs when taken intraperitoneally. Pepstatin A (0.5–50 mg/kg, p.o.) inhibits the pylorus-induced stomach ulceration in ligated Shay rats.
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| Enzyme Assay |
Pepstatin A is a well-known aspartic proteinase inhibitor; its IC50 values for human renin, HIV protease, pepsin, and cathepsin D are 15 μM, 2 μM, < 5 nM, and < 40 nM, respectively.
The protease encoded by the human immunodeficiency virus (HIV) processes the viral gag and gag-pol protein precursor by posttranslational cleavage. In this study we have demonstrated by site-specific mutagenesis (Asp----Thr) and by pepstatin A inhibition that the recombinant HIV protease is an aspartic-type protease. Furthermore, incubation of HIV-infected H9 cells with pepstatin A inhibited part of the intracellular processing of the HIV gag protein yet had no apparent toxicity on HIV-infected cells during 48 hr of incubation.[1] |
| Cell Assay |
Pepstatin A is freshly dissolved in DMSO at 7 mM. It is very slowly diluted (1:100) into the medium of HIV-infected H9 suspension cultures so that no pepstatin A precipitated (final concentration, 70 μM pepstatin A and 1% DMSO), and the cultures are incubated without change of culture medium for 48 hr. As control, uninfected H9 cells are also incubated with pepstatin and in addition HIV infected and uninfected cells are incubated with 1% DMSO but without pepstatin[1].
Pepstatin A is well known to be an inhibitor of aspartic proteinases such as pepsin, cathepsins D and E. Except for its role as a proteinase inhibitor, however, the pharmacological action of pepstatin A upon cells remain unclear. In this study, we found that pepstatin A suppressed receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation. Pepstatin A suppressed the formation of multinuclear osteoclasts dose-dependently. This inhibition of the formation only affected osteoclast cells, i.e., not osteoblast-like cells. Furthermore, pepstatin A also suppressed differentiation from pre-osteoclast cells to mononuclear osteoclast cells dose-dependently. This inhibition seems to be independent of the activities of proteinases such as cathepsin D, because the formation of osteoclasts was not suppressed with the concentration that inhibited the activity of cathepsin D. Cell signaling analysis indicated that the phosphorylation of ERK was inhibited in pepstatin A-treated cells, while the phosphorylation of IkappaB and Akt showed almost no change. Furthermore, pepstatin A decreased the expression of nuclear factor of activated T cells c1 (NFATc1). These results suggest that pepstatin A suppresses the differentiation of osteoclasts through the blockade of ERK signaling and the inhibition of NFATc1 expression.[2] |
| Animal Protocol |
Pylorus ligated male Wistar rats
0.5, 1, 10 and 50 mg/kg Oral administration, 15 minutes after pyloric ligation |
| Toxicity/Toxicokinetics |
rat LD50 oral >2 gm/kg Proceedings of the International Symposium of the Princess Takamatsu Cancer Research Fund., 6(57), 1976
mouse LD50 oral >2 gm/kg Proceedings of the International Symposium of the Princess Takamatsu Cancer Research Fund., 6(57), 1976 dog LD50 oral >2 gm/kg Journal of Antibiotics., 23(259), 1970 [PMID:4912600] dog LD50 intraperitoneal 450 mg/kg Journal of Antibiotics., 23(259), 1970 [PMID:4912600] rabbit LD50 oral >2 gm/kg Journal of Antibiotics., 23(259), 1970 [PMID:4912600] |
| References | |
| Additional Infomation |
Pepstatin A is a pentapeptide isolated from Streptomyces testaceus. It is a potent inhibitor of aspartyl proteases. It has a role as a bacterial metabolite and an EC 3.4.23.* (aspartic endopeptidase) inhibitor. It is a pentapeptide and a secondary carboxamide. It is a conjugate acid of a pepstatin A(1-).
Pepstatin has been reported in Streptomyces with data available. |
| Molecular Formula |
C34H63N5O9
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| Molecular Weight |
685.89
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| Exact Mass |
685.462
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| Elemental Analysis |
C, 59.54; H, 9.26; N, 10.21; O, 20.99
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| CAS # |
26305-03-3
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| Related CAS # |
28575-34-0
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| PubChem CID |
5478883
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| Sequence |
IsoValeryl-Val-Val-Sta-Ala-Sta-OH
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| SequenceShortening |
IsoVeryl-VV-Sta-A-Sta-OH
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
997.6±65.0 °C at 760 mmHg
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| Melting Point |
233 °C (dec.)(lit.)
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| Flash Point |
557.1±34.3 °C
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| Vapour Pressure |
0.0±0.6 mmHg at 25°C
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| Index of Refraction |
1.504
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| Source |
Actinomycetes
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| LogP |
2.16
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| Hydrogen Bond Donor Count |
8
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
22
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| Heavy Atom Count |
48
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| Complexity |
1060
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| Defined Atom Stereocenter Count |
7
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| SMILES |
O([H])[C@@]([H])(C([H])([H])C(N([H])[C@@]([H])(C([H])([H])[H])C(N([H])[C@]([H])([C@]([H])(C([H])([H])C(=O)O[H])O[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)[C@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)=O
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| InChi Key |
FAXGPCHRFPCXOO-LXTPJMTPSA-N
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| InChi Code |
InChI=1S/C34H63N5O9/c1-17(2)12-23(37-33(47)31(21(9)10)39-34(48)30(20(7)8)38-27(42)14-19(5)6)25(40)15-28(43)35-22(11)32(46)36-24(13-18(3)4)26(41)16-29(44)45/h17-26,30-31,40-41H,12-16H2,1-11H3,(H,35,43)(H,36,46)(H,37,47)(H,38,42)(H,39,48)(H,44,45)/t22-,23-,24-,25-,26-,30-,31-/m0/s1
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| Chemical Name |
(3S,4S)-3-hydroxy-4-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(3-methylbutanoylamino)butanoyl]amino]butanoyl]amino]heptanoyl]amino]propanoyl]amino]-6-methylheptanoic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (3.03 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5 mg/mL (7.29 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4580 mL | 7.2898 mL | 14.5796 mL | |
| 5 mM | 0.2916 mL | 1.4580 mL | 2.9159 mL | |
| 10 mM | 0.1458 mL | 0.7290 mL | 1.4580 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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