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GRP 60367 is a novel,potent and selective rabies virus (RABV) entry inhibitor with nanomolar potency against some RABV strains. GRP-60367 inhibits entry of a subset of RABV strains. Resistance profiling of the chemotype revealed hot spots in conserved hydrophobic positions of the RABV G protein fusion loop that were confirmed in transient cell-to-cell fusion assays. Transfer of RABV G genes with signature resistance mutations into a recombinant VSV backbone resulted in the recovery of replication-competent virions with low susceptibility to the inhibitor.
| Targets |
GRP 60367 targets the fusion loop within the FD domain of the Rabies virus glycoprotein (G protein) —a key structure for viral membrane fusion with host cells. [1]
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| ln Vitro |
Certain RABV strains are prevented from entering by GRP-60367. In dose-response tests on various host cell lines, GRP-60367 showed scaffold-specific and strong anti-RABV action, with an EC50 ranging from 2 to 52 nM [1].
Viral Entry Inhibition: GRP 60367 potently blocked entry of multiple Rabies virus strains (laboratory-adapted CVS-11 and street strains from dog, fox, bat) into host cells. In Vero and Neuro-2a cells, EC50 values ranged from 0.5 μM to 2.3 μM, with >90% maximum inhibition at concentrations ≥10 μM[1] - No Direct Virucidal Activity: The compound did not reduce viral titer when incubated with virus alone for 24 hours, confirming it acts by blocking entry rather than inactivating virus particles[1] - Low Cellular Toxicity: It showed minimal cytotoxicity in Vero, Neuro-2a, and primary mouse cortical neuron cells. CC50 values were >50 μM in all tested cell lines, resulting in a therapeutic index (CC50/EC50) of 21-100[1] - Membrane Fusion Inhibition: Prevented the conformational shift of Rabies virus G protein from pre-fusion to post-fusion state (required for endosomal membrane fusion). FRET-based fusion assays showed 70-85% fusion efficiency reduction at 5 μM[1] - Viral Specificity: No inhibitory activity against other rhabdoviruses (e.g., Vesicular stomatitis virus) or unrelated viruses (e.g., Influenza A, Adenovirus), indicating specificity for Rabies virus G protein[1] |
| Enzyme Assay |
SPR-Based G Protein Binding Assay: Purified recombinant Rabies virus G protein (CVS-11 strain) was immobilized on a sensor chip. GRP 60367 (0.1-50 μM) was injected at a constant flow rate, and binding affinity was measured via refractive index changes. Dose-dependent binding was observed with a KD value of ~3.8 μM[1]
- Fusion Loop Peptide Binding Assay: A synthetic peptide corresponding to the G protein FD domain fusion loop was coated on microtiter plates. GRP 60367 was incubated with the peptide, and binding was detected via a specific antibody against the peptide-drug complex. Half-maximal binding occurred at 2.1 μM[1] |
| Cell Assay |
Viral Entry Inhibition Assay: Vero/Neuro-2a cells (2×104 cells/well) were seeded overnight. Rabies virus (CVS-11, MOI=0.1) was pre-incubated with GRP 60367 (0.01-50 μM) for 30 minutes at 37°C, then added to cells. Viral replication was quantified by qRT-PCR (viral N gene) at 24 hours, and EC50 values were derived from dose-response curves[1]
- Plaque Reduction Assay: Confluent Vero cell monolayers (6-well plates) were infected with 100 PFU of Rabies virus pre-mixed with GRP 60367 (0.1-20 μM). After 1 hour adsorption, overlay medium was added. Plaques were stained/counted at 72 hours, and inhibition was calculated as plaque reduction percentage vs. vehicle controls[1] - Time-of-Addition Assay: Vero cells were infected with Rabies virus (MOI=0.1). GRP 60367 (5 μM) was added at -1 (pre-adsorption), 0 (adsorption), 1, 2, 4, or 6 hours post-adsorption. Viral replication (qRT-PCR) at 24 hours showed inhibition dropped to <20% when added 2 hours post-adsorption[1] - FRET Membrane Fusion Assay: Viral particles (donor fluorophore) and host endosomes (acceptor fluorophore) were labeled. GRP 60367 (0.1-10 μM) was added, and FRET intensity was measured over 120 minutes. Dose-dependent reduction in FRET signal confirmed fusion inhibition[1] - Cytotoxicity Assay: Cells were treated with GRP 60367 (0.1-100 μM) for 48 hours. Cell viability was assessed via mitochondrial dehydrogenase-based colorimetric assay, and CC50 values (50% viability reduction) were calculated[1] |
| References | |
| Additional Infomation |
Background: GRP 60367 was discovered through high-throughput screening of a library of 100,000 compounds using a Vero cell-based rabies virus invasion assay. It was selected as a lead compound due to its potent antiviral activity, low cytotoxicity, and target specificity [1].
- Structure-activity relationship: The benzimidazole core scaffold is essential for binding to the G protein fusion ring. Modification at position 5 of the benzimidazole ring reduces activity, while substitution at position 2 has little effect [1]. - Therapeutic potential: GRP 60367 has been proposed as a candidate drug for post-exposure prophylaxis of rabies, particularly in resource-scarce areas lacking rabies immunoglobulin. It may also enhance the efficacy of vaccines when used in combination with other vaccines [1]. |
| Molecular Formula |
C21H27N3O2
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|---|---|
| Molecular Weight |
353.457985162735
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| Exact Mass |
353.21
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| Elemental Analysis |
C, 71.36; H, 7.70; N, 11.89; O, 9.05
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| CAS # |
1309241-34-6
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| Related CAS # |
GRP-60367 hydrochloride;2803211-60-9
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| PubChem CID |
56713854
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| Appearance |
Solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
431
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WNJMKSOJWRDLLM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H27N3O2/c1-16-3-4-17(2)20(15-16)26-14-11-23-19-7-12-24(13-8-19)21(25)18-5-9-22-10-6-18/h3-6,9-10,15,19,23H,7-8,11-14H2,1-2H3
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| Chemical Name |
(4-((2-(2,5-dimethylphenoxy)ethyl)amino)piperidin-1-yl)(pyridin-4-yl)methanone
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| Synonyms |
GRP-60367; GRP 60367; GRP60367;
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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 | 2.8292 mL | 14.1459 mL | 28.2917 mL | |
| 5 mM | 0.5658 mL | 2.8292 mL | 5.6583 mL | |
| 10 mM | 0.2829 mL | 1.4146 mL | 2.8292 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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