| Size | Price | Stock | Qty |
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| 10mg |
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| 100mg | |||
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| Targets |
HIV; nucleoside reverse transcriptase translocation
HIV-1 reverse transcriptase (RT). As an NRTTI, MK‑8527 works by a dual mechanism: it inhibits the translocation of the reverse transcriptase enzyme along the viral RNA/DNA template, thereby blocking DNA synthesis. It has a similar inhibitory mechanism to islatravir (ISL). |
|---|---|
| ln Vitro |
MK-8527 inhibits HIV via same mechanism as that of Islatravir (ISL) may supersede Islatravir (ISL). Data on ISL inhibition of HBV are scarce, and preclinical data show dramatically lower ISL efficacy against HBV than currently preferred nucleos(t)ide drugs, indicating that ISL may not be a potent anti-HBV drug.[1]
In cell‑free assays, MK‑8527 has an IC50 of 0.21 nM against HIV‑1 reverse transcriptase. It is a potent antiviral agent with high activity against a broad range of HIV‑1 isolates. In cellular assays, it exhibits potent anti‑HIV activity with EC50 values in the low nanomolar range. The compound is intracellularly metabolized to its active triphosphate form, which is the actual inhibitor of reverse transcriptase. |
| ln Vivo |
In vivo, MK‑8527 has been evaluated in phase I clinical trials in healthy adults. It is designed as a long‑acting agent for once‑monthly oral administration. Animal studies have demonstrated its efficacy in preventing HIV infection when dosed intermittently, supporting its development as a long‑acting PrEP agent.
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| Enzyme Assay |
Additionally, MK-8527 has a similar mechanism of inhibition to that of Islatravir (ISL), and is currently in Phase I clinical trials, suggesting that developers are finding ways to improve upon ISL. Therefore, MK-8527 May supersede and replace ISL.[1]
A general cell‑free protocol for measuring reverse transcriptase translocation inhibition: Recombinant HIV‑1 RT is incubated with an RNA/DNA primer/template, dNTPs, and the active triphosphate form of MK‑8527. The reaction mixture is analyzed by a primer extension assay using denaturing PAGE. The pattern of chain termination products is compared to that of a control to determine the mechanism of inhibition. |
| Cell Assay |
A general cellular protocol for measuring anti-HIV activity: TZM‑bl cells are infected with HIV‑1 and cultured with serial dilutions of MK‑8527. After 48 hours, the cells are lysed, and the amount of luciferase activity (driven by the HIV long terminal repeat (LTR) promoter) is measured. The EC50 is calculated. Cytotoxicity is determined in uninfected cells using the MTT assay.
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| Animal Protocol |
A general animal protocol for a long-acting PrEP agent: Humanized bone marrow‑liver‑thymus (BLT) mice are challenged vaginally or rectally with HIV‑1. MK‑8527 is administered orally once monthly at doses of 10, 50, and 250 mg/kg. The mice are monitored for several weeks for viral infection by measuring plasma viral load. Efficacy is determined by comparing the number of infected animals and viral load between treatment and control groups.
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| ADME/Pharmacokinetics |
General PK protocol for MK-8527: A phase I clinical study has been conducted in healthy adults without HIV. Participants received single oral doses of MK‑8527 (0.5‑200 mg) after fasting, and a 25 mg dose was also assessed after a high‑fat meal. Plasma concentrations of MK‑8527 and its active triphosphate anabolite were measured to determine PK parameters such as Cmax, Tmax, AUC, and half‑life.
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| Toxicity/Toxicokinetics |
General toxicity protocol for MK-8527: In phase I trials, MK‑8527 was generally well‑tolerated at single doses up to 200 mg and multiple doses up to 50 mg. The most common adverse events were gastrointestinal (nausea, diarrhea) and headache. The QT interval was monitored to assess cardiac safety. Longer‑term toxicity studies in animals would be required for regulatory approval.
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| References | |
| Additional Infomation |
Introduction Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV reverse transcriptase through multiple mechanisms. Unlike all approved NRTTIs, islatravir retains the 3'-hydroxyl group. In vitro and clinical data suggest that ISL is a highly tolerable and potent investigational drug. This article reviews the historical development of islatravir and its mechanisms of action against HIV and HBV and drug resistance. Furthermore, the results of Phase I and Phase II clinical trials are discussed. Expert Opinion Current first-line antiretroviral therapies, pre-exposure prophylaxis, and post-exposure prophylaxis interventions are highly effective in maintaining low or undetectable viral loads. Despite these measures, the exceptionally high annual rate of new infections continues to drive the development of novel antiretroviral drugs that can inhibit drug-resistant HIV and improve patient adherence. ISL was once considered a long-acting drug, but clinical trials have been suspended. The results of ongoing clinical trials of reduced-dose ISL will determine its future clinical application. In addition, MK-8527 inhibits HIV through the same mechanism as ISL and may replace ISL. There is little data on the inhibition of HBV by ISL, and preclinical data show that the efficacy of ISL against HBV is far lower than that of the currently preferred nucleoside (acid) analogues, suggesting that ISL may not be an effective anti-HBV drug. [1]
A phase III clinical trial (MK‑8527‑011) is currently evaluating the efficacy and safety of oral, once‑monthly MK‑8527 for HIV‑1 pre‑exposure prophylaxis (PrEP). The goals of the study are to determine if MK‑8527 works as well as or better than standard daily PrEP. It is designed to be a convenient, long‑acting prevention option. The compound is also known as MK-8527 and has a CAS number of 1810869-23-8. |
| Molecular Formula |
C13H13CLN4O3
|
|---|---|
| Molecular Weight |
308.72
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| Exact Mass |
308.068
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| CAS # |
1810869-23-8
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| PubChem CID |
118389446
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
21
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| Complexity |
458
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| Defined Atom Stereocenter Count |
3
|
| SMILES |
C#C[C@]1([C@H](C[C@@H](O1)N2C=CC3=C(N=C(N=C32)Cl)N)O)CO
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| InChi Key |
QNBRWIDODCWXKA-IGJMFERPSA-N
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| InChi Code |
InChI=1S/C13H13ClN4O3/c1-2-13(6-19)8(20)5-9(21-13)18-4-3-7-10(15)16-12(14)17-11(7)18/h1,3-4,8-9,19-20H,5-6H2,(H2,15,16,17)/t8-,9+,13+/m0/s1
|
| Chemical Name |
(2R,3S,5R)-5-(4-amino-2-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)oxolan-3-ol
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| Synonyms |
MK-8527; MK8527
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 3.2392 mL | 16.1959 mL | 32.3918 mL | |
| 5 mM | 0.6478 mL | 3.2392 mL | 6.4784 mL | |
| 10 mM | 0.3239 mL | 1.6196 mL | 3.2392 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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