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Avexitide [Exendin-3 (9-39)] is a novel, competitive and peptidic antagonist of glucagon-like peptide-1 (GLP-1) receptor with a Kd of 1.7 nM at cloned human GLP-1 receptors. Exendin (9–39) blocks the release of insulin and the synthesis of cAMP that is triggered by GLP-1 (7–36), exendin-3, and exendin-4.
| Targets |
GLP-1 receptor
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|---|---|
| ln Vitro |
GLP-1 is involved in the regulation of fasting glucose. Avexitide (also known as Exendin (9-39)) is a particular GLP-1 receptor antagonist that is derived from a shortened version of the GLP-1 agonist exendin-4[1].
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| ln Vivo |
In SUR-1 -/- mice, continuous subcutaneous infusion of Avexitide (Exendin (9-39)) dramatically increases fasting blood glucose levels without compromising glucose tolerance[2].
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| Enzyme Assay |
cAMP Content Determination—Islets were isolated as above, hand-picked, and cultured for 3 days. Cultured islets were preincubated in glucose-free Krebs-Ringer bicarbonate buffer for 60 min, and 100 nm exendin-(9–39) was added 30 min into the preincubation period. Then, islets were exposed to different treatments for an additional 30 min in the presence of 0.1 mm isobutylmethylzanthine. After incubation, islets were washed two times by cold glucose-free Hanks' buffer. cAMP was measured in islet lysates by an enzyme-linked immunosorbent assay[2].
Cytosolic Free Ca2+ Measurements—Mouse islets were isolated and cultured on poly-l-lysine-coated glass coverslips under the same conditions as described above. The perifusion procedure and cytosolic-free Ca2+ ([Ca2+]i) measurement were described previously. In brief, the coverslip with attached islets was incubated with 15 μm Fura-2 acetoxymethylester in Krebs-Ringer bicarbonate buffer with 5 mm glucose for 35 min at 37 °C. Islets were then perifused with Krebs-Ringer bicarbonate buffer with 0.25% bovine serum albumin at 37 °C at a flow rate of 2 ml/min while various agents were applied. [Ca2+]i was measured with a dual wavelength fluorescence microscope as previously described[2]. |
| Cell Assay |
Islet Studies—Islets were isolated by collagenase digestion and cultured for 3 days in RPMI 1640 medium containing 10 mm glucose. The culture medium was supplemented with 10% fetal bovine serum, 2 mm glutamine, 100 units/ml penicillin, and 50 μg/ml streptomycin. Islets were incubated at 37 °C in a 5% CO2, 95% air-humidified incubator. Batches of 100 cultured mouse islets were loaded onto a nylon filter in a chamber and perifused with Krebs-Ringer bicarbonate buffer (115 mm NaCl, 24 mm NaHCO3, 5 mm KCl, 1 mm MgCl2, 2.5 mm CaCl2, 10 mm HEPES, pH 7.4) with 0.25% bovine serum albumin at a flow rate of 2 ml/min. Perifusate solutions were gassed with 95% O2, 5% CO2 and maintained at 37 °C. Islets were stimulated with a ramp of amino acids. The mixture of 19 amino acids when used at a maximum concentration of 12 mm (about 3 times physiological concentration) had the following composition: 2 mm glutamine, 1.25 mm alanine, 0.53 mm arginine, 0.11 mm aspartate, 0.27 mm citrulline, 0.35 mm glutamate, 0.85 mm glycine, 0.22 mm histidine, 0.27 mm isoleucine, 0.46 mm leucine, 1.06 mm lysine, 0.14 mm methionine, 0.20 mm ornithine, 0.23 mm phenylalanine, 1 mm proline, 1.62 mm serine, 0.77 mm threonine, 0.21 mm tryptophan, 0.57 mm valine. Samples were collected every minute for insulin assays. Insulin was measured by radioimmunoassay[2].
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| Animal Protocol |
Mice: Avexitide (Exendin (9-39)) or a vehicle (0.9% NaCl, 1% bovine serum albumin) is administered subcutaneously via Alzet miniosmotic pumps for a period of two weeks[2].
Exendin-(9–39) Administration—Alzet miniosmotic pumps were implanted subcutaneously to deliver exendin-(9–39) at a rate of 150 pmol/kg/min or vehicle (0.9% NaCl, 1% bovine serum albumin) for 2 weeks.[2] Glucose Homeostasis—For determination of fasting blood glucose levels, mice were fasted for 12–16 h. Oral glucose tolerance testing was carried after a 12–16-h fast by administering 2 g/kg of dextrose by oral gavage (feeding needles). For insulin tolerance testing, mice received 0.5 units/kg of insulin intraperitoneally after a 4-h fast. Blood glucose levels were measured using a hand-held glucose meter. Insulin and glucagon were measured by ELISA.[2] |
| References |
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| Additional Infomation |
Avexitide is under investigation in clinical trial NCT02996812 (Evaluation of Single Ascending Doses of Subcutaneous Exendin 9-39 in Patients With Post-Bariatric Hypoglycemia).
Avexitide is a truncated form of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 peptide, with GLP-1 receptor (GLP-1R) antagonistic and GLP-1R-mediated signaling inhibiting activities. Upon administration, avexitide competitively binds to and inhibits the activity of GLP-1R, thereby inhibiting GLP-1/GLP-1R-mediated signaling. This antagonizes the glucagonostatic and the insulinotropic effects of GLP-1. By abrogating GLP-1-mediated simulation of insulin release and reduction of glucagon secretion after food intake, exendin 9-39 may be used to help study the potential effects of overproduction of GLP-1 on food intake, weight loss and glucose levels. GLP-1R, located on pancreatic beta cells, is overexpressed on certain tumor cell types. GLP-1 is a gastrointestinal (GI) and insulinotropic hormone that is released after a meal and plays a key role in the regulation of blood glucose levels. See also: Avexitide (annotation moved to). |
| Molecular Formula |
C₁₄₉H₂₃₄N₄₀O₄₇S
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|---|---|
| Molecular Weight |
3369.76
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| Exact Mass |
3367.687
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| Elemental Analysis |
C, 53.11; H, 7.00; N, 16.63; O, 22.31; S, 0.95
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| CAS # |
133514-43-9
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| Related CAS # |
2051593-46-3 (acetate); 133514-43-9
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| PubChem CID |
16198321
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| Sequence |
Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
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| SequenceShortening |
DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
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| Appearance |
Off-white to pale purple solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.671
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| LogP |
-5.88
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| Hydrogen Bond Donor Count |
45
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| Hydrogen Bond Acceptor Count |
52
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| Rotatable Bond Count |
109
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| Heavy Atom Count |
237
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| Complexity |
8000
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| Defined Atom Stereocenter Count |
29
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| SMILES |
[DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2]
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| InChi Key |
WSEVKKHALHSUMB-MVNVRWBSSA-N
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| InChi Code |
InChI=1S/C149H234N40O47S/c1-14-78(10)120(185-139(227)98(62-81-29-16-15-17-30-81)177-136(224)97(61-76(6)7)175-129(217)88(35-24-53-158-149(156)157)172-144(232)119(77(8)9)184-122(210)79(11)164-126(214)90(41-46-114(199)200)168-131(219)91(42-47-115(201)202)169-132(220)92(43-48-116(203)204)170-134(222)94(50-58-237-13)171-130(218)89(40-45-109(153)194)167-127(215)86(33-20-22-51-150)166-140(228)103(72-192)182-137(225)95(59-74(2)3)174-123(211)84(152)64-118(207)208)145(233)173-93(44-49-117(205)206)133(221)178-99(63-82-66-159-85-32-19-18-31-83(82)85)138(226)176-96(60-75(4)5)135(223)165-87(34-21-23-52-151)128(216)179-100(65-110(154)195)124(212)161-67-111(196)160-69-113(198)186-54-25-36-105(186)142(230)183-104(73-193)141(229)181-102(71-191)125(213)162-68-112(197)163-80(12)146(234)188-56-27-38-107(188)148(236)189-57-28-39-108(189)147(235)187-55-26-37-106(187)143(231)180-101(70-190)121(155)209/h15-19,29-32,66,74-80,84,86-108,119-120,159,190-193H,14,20-28,33-65,67-73,150-152H2,1-13H3,(H2,153,194)(H2,154,195)(H2,155,209)(H,160,196)(H,161,212)(H,162,213)(H,163,197)(H,164,214)(H,165,223)(H,166,228)(H,167,215)(H,168,219)(H,169,220)(H,170,222)(H,171,218)(H,172,232)(H,173,233)(H,174,211)(H,175,217)(H,176,226)(H,177,224)(H,178,221)(H,179,216)(H,180,231)(H,181,229)(H,182,225)(H,183,230)(H,184,210)(H,185,227)(H,199,200)(H,201,202)(H,203,204)(H,205,206)(H,207,208)(H4,156,157,158)/t78-,79-,80-,84-,86-,87-,88-,89-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,119-,120-/m0/s1
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| Chemical Name |
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-5-oxopentanoyl]amino]-4-methylsulfanylbutanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-4-amino-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
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| Synonyms |
Exendin 9-39; Avexitide Free Base; Exendin (9-39); Avexitide; Exendin-3 (9-39); Asp-LEU-SER-LYS-GLN-MET-GLU-GLU-GLU-ALA-VAL-ARG-LEU-PHE-ILE-GLU-TR; p; -LEU-LYS-ASN-GLY-GLY-PRO-SER-SER-GLY-ALA-PRO-PRO-PRO-SER-NH2; ASP-LEU-SER-LYS-GLN-MET-GLU-GLU-GLU-ALA-VAL-ARG-LEU-PHE-ILE-GLU-TRP-LEU-LYS-ASN-GLY-GLY-PRO-SER-SER-; Exendin-(9-39)
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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. |
| 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) |
H2O: ~50 mg/mL (~14.8 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (29.68 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2968 mL | 1.4838 mL | 2.9676 mL | |
| 5 mM | 0.0594 mL | 0.2968 mL | 0.5935 mL | |
| 10 mM | 0.0297 mL | 0.1484 mL | 0.2968 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03373435 | Completed | Drug: exendin 9-39 Other: Placebo |
Postbariatric Hypoglycemia | Eiger BioPharmaceuticals | March 19, 2018 | Phase 2 |
| NCT02971631 | Completed | Other: Exendin 9-39 Other: Placebo |
Gastric Cancer Dumping Syndrome |
Cambridge University Hospitals NHS Foundation Trust |
August 10, 2017 | Not Applicable |
| NCT01795144 | Completed | Drug: GLP-1 Drug: Exendin 9-39 |
Monogenic Diabetes | University of Chicago | January 2014 | Phase 1 |
| NCT02336659 | Completed | Drug: exendin 9-39 Drug: sitagliptin |
Severe Obesity | Hvidovre University Hospital | April 2014 | Not Applicable |
| NCT02771574 | Completed | Drug: Lyo avexitide Drug: Liq avexitide |
Post Bariatric Hypoglycemia | Tracey McLaughlin | May 2016 | Phase 2 |
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