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| Targets |
STAD-2 targets the regulatory subunit II (RII) of protein kinase A (PKA). PKA is a tetrameric holoenzyme composed of two catalytic subunits and two regulatory subunits. The regulatory subunits (RI and RII) bind to the catalytic subunits and inhibit their activity in the absence of cAMP. Upon cAMP binding, the regulatory subunits dissociate from the catalytic subunits, releasing active PKA. AKAPs bind to the dimerization/docking (D/D) domain of the RII subunit, anchoring PKA to specific subcellular locations, such as the plasma membrane, mitochondria, or nucleus. STAD-2 is a peptide that mimics the AKAP binding site and competitively binds to the D/D domain of the RII subunit with a Kd of 6.2 nM, thereby disrupting the PKA-AKAP interaction. This disruption prevents the anchoring of PKA to its subcellular targets, thereby modulating compartmentalized PKA signaling without affecting total PKA activity.
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| ln Vitro |
In vitro, STAD-2 inhibits the binding of PKA-RII to AKAPs in pull-down assays and co-immunoprecipitation experiments. The compound's binding affinity for the RII subunit has been characterized by surface plasmon resonance and isothermal titration calorimetry, showing a Kd of 6.2 nM. STAD-2 is selective for the RII subunit over the RI subunit, providing isoform-selective disruption of PKA anchoring. In cellular assays, STAD-2 disrupts the localization of PKA to specific cellular compartments, as demonstrated by fluorescence microscopy using fluorescently labeled PKA subunits or AKAPs. The compound's effects on downstream PKA signaling are context-dependent, as they depend on the specific AKAP-PKA complexes that are disrupted. In addition to its effects on PKA signaling, STAD-2 has been shown to exhibit antimalarial activity in vitro, suggesting that it may have additional targets or mechanisms of action.
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| ln Vivo |
In vivo, STAD-2 has been studied for its antimalarial activity, showing efficacy in mouse models of malaria. The compound's antimalarial effect is thought to be mediated through a PKA-independent mechanism, as the compound inhibits Plasmodium growth in a manner that is not correlated with its effects on PKA anchoring. The specific target of STAD-2 in Plasmodium has not been identified, but the compound's ability to inhibit parasite growth in vivo makes it a potential lead for antimalarial drug development. In addition to its antimalarial activity, STAD-2 is used as a research tool to study the role of PKA-AKAP interactions in various physiological and pathological processes, including cardiac function, neuronal signaling, and immune regulation.
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| Enzyme Assay |
The non-cellular assay for STAD-2 involves measuring the binding of the peptide to the PKA-RII subunit using surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), or fluorescence polarization. In a typical SPR assay, the RII subunit or its D/D domain is immobilized on a sensor chip, and varying concentrations of STAD-2 are flowed over the chip. The binding kinetics (association rate, dissociation rate, and affinity) are determined from the sensorgrams. In a fluorescence polarization assay, a fluorescently labeled AKAP peptide is incubated with the RII subunit in the presence of varying concentrations of STAD-2. The displacement of the labeled peptide by STAD-2 results in a decrease in fluorescence polarization, and the IC50 is determined. The binding affinity (Kd) is calculated from the competition data.
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| Cell Assay |
The cellular assay for STAD-2 involves treating cultured cells with the peptide and assessing the disruption of PKA-AKAP interactions and the effects on PKA signaling. Cells are transfected with fluorescently tagged PKA subunits or AKAPs, and the localization of PKA is visualized by fluorescence microscopy. Treatment with STAD-2 results in the redistribution of PKA from its anchored locations to the cytosol. In addition, the effects of STAD-2 on PKA-dependent phosphorylation of downstream targets (such as CREB) are assessed by Western blotting using phospho-specific antibodies. The compound's effects on cell proliferation, apoptosis, or other cellular functions are also evaluated. For antimalarial studies, Plasmodium falciparum cultures are treated with STAD-2, and parasite growth is measured by [³H]-hypoxanthine incorporation or by microscopy.
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| Animal Protocol |
The in vivo animal studies for STAD-2 typically use mouse models of malaria. Mice are infected with Plasmodium berghei or Plasmodium yoelii, and STAD-2 is administered intraperitoneally or orally at various doses (typically 1-50 mg/kg) daily for several days. Parasitemia is monitored by blood smear microscopy, and the survival rate is recorded. The efficacy of STAD-2 is compared to that of standard antimalarial drugs, such as chloroquine or artemisinin. In addition to antimalarial studies, STAD-2 is used in models of cardiac function, neuronal signaling, or other processes where PKA-AKAP interactions are important. The compound is administered by injection or infusion, and its effects on physiology or behavior are assessed.
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| ADME/Pharmacokinetics |
STAD-2 has a molecular weight of 2096.72 g/mol and a molecular formula of C₁₀₂H₁₈₂N₂₄O₂₂. It is a peptide and is therefore susceptible to degradation by proteases. The compound should be stored as a powder at -20°C, protected from light and moisture. For in vivo studies, STAD-2 may require formulation with protease inhibitors or in a delivery system to improve its stability and bioavailability.
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| Toxicity/Toxicokinetics |
STAD-2 is generally well-tolerated in preclinical studies at the doses used for antimalarial and PKA signaling studies. However, as a peptide, it may have immunogenic potential and is susceptible to proteolytic degradation. Comprehensive toxicology data are limited, and the compound is not approved for clinical use. STAD-2 should be handled with appropriate laboratory safety precautions.
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| References | |
| Additional Infomation |
STAD-2 is a potent and specific peptide disruptor of PKA-AKAP interactions, providing a unique tool for studying compartmentalized cAMP signaling. Its high affinity for the PKA-RII subunit (Kd = 6.2 nM) and isoform-selective disruption of PKA anchoring make it a valuable research tool for elucidating the roles of AKAPs in health and disease. In addition to its use in PKA signaling research, STAD-2 has shown antimalarial activity through a PKA-independent mechanism, suggesting potential applications in infectious disease research. The compound continues to be studied for its therapeutic potential and as a research tool for understanding the role of PKA-AKAP interactions in various biological processes.
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| Molecular Formula |
C102H182N24O22
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|---|---|
| Molecular Weight |
2096.68410539627
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| Exact Mass |
2095.386
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| CAS # |
1542100-77-5
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| PubChem CID |
146018942
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| Appearance |
White to off-white solid powder
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
25
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| Hydrogen Bond Acceptor Count |
28
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| Rotatable Bond Count |
68
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| Heavy Atom Count |
148
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| Complexity |
4110
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| Defined Atom Stereocenter Count |
17
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| SMILES |
[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@]1(CCCC=CCCC[C@@](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC1=O)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N)CCCCN)C)(NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)COCCOCCOCCN)CC1C=CC=CC=1 |c:29,&1:0,4,12,19,25,34,38,47,55,64,69,77,90,99,104,112,121|
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| InChi Key |
FREADERNJMYCAI-LLUHBCIQSA-N
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| InChi Code |
InChI=1S/C102H182N24O22/c1-62(2)55-76(120-90(135)74(40-26-33-47-106)116-88(133)72(38-24-31-45-104)113-82(128)61-148-54-53-147-52-51-146-50-49-108)91(136)110-67(11)85(130)115-73(39-25-32-46-105)89(134)122-80(59-70-35-21-20-22-36-70)94(139)121-79(58-65(7)8)95(140)124-83(66(9)10)98(143)123-81(60-127)97(142)126-102(15)43-29-19-17-16-18-28-42-101(14,99(144)111-68(12)86(131)118-77(56-63(3)4)92(137)114-71(84(109)129)37-23-30-44-103)125-96(141)75(41-27-34-48-107)117-93(138)78(57-64(5)6)119-87(132)69(13)112-100(102)145/h16-17,20-22,35-36,62-69,71-81,83,127H,18-19,23-34,37-61,103-108H2,1-15H3,(H2,109,129)(H,110,136)(H,111,144)(H,112,145)(H,113,128)(H,114,137)(H,115,130)(H,116,133)(H,117,138)(H,118,131)(H,119,132)(H,120,135)(H,121,139)(H,122,134)(H,123,143)(H,124,140)(H,125,141)(H,126,142)/b17-16+/t67-,68-,69-,71-,72-,73-,74-,75-,76-,77-,78-,79-,80-,81-,83-,101-,102-/m0/s1
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| Chemical Name |
(2S,5S,8S,11S,15E,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-8-(4-aminobutyl)-N-[(2S)-1-[[(2S)-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]-2,11,20-trimethyl-5-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-ene-11-carboxamide
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| Synonyms |
STAD2; STAD 2; STAD-2
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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) |
DMSO : ≥ 100 mg/mL (~47.69 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.4769 mL | 2.3847 mL | 4.7694 mL | |
| 5 mM | 0.0954 mL | 0.4769 mL | 0.9539 mL | |
| 10 mM | 0.0477 mL | 0.2385 mL | 0.4769 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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