Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Mar 25

PMID 35328566

Authors

Amaresh K Ranjan

Anil Gulati

Affiliations

Soon will be listed here.

Abstract

Neurological/neurovascular disorders constitute the leading cause of disability and the second leading cause of death globally. Major neurological/neurovascular disorders or diseases include cerebral stroke, Alzheimer's disease, spinal cord injury, neonatal hypoxic-ischemic encephalopathy, and others. Their pathophysiology is considered highly complex and is the main obstacle in developing any drugs for these diseases. In this review, we have described the endothelin system, its involvement in neurovascular disorders, the importance of endothelin B receptors (ETBRs) as a novel potential drug target, and its agonism by IRL-1620 (INN-sovateltide), which we are developing as a drug candidate for treating the above-mentioned neurological disorders/diseases. In addition, we have highlighted the results of our preclinical and clinical studies related to these diseases. The phase I safety and tolerability study of sovateltide has shown it as a safe and tolerable compound at therapeutic dosages. Furthermore, preclinical and clinical phase II studies have demonstrated the efficacy of sovateltide in treating acute ischemic stroke. It is under development as a first-in-class drug. In addition, efficacy studies in Alzheimer's disease (AD), acute spinal cord injury, and neonatal hypoxic-ischemic encephalopathy (HIE) are ongoing. Successful completion of these studies will validate that ETBRs signaling can be an important target in developing drugs to treat neurological/neurovascular diseases.

Citing Articles

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Structure of endothelin ET receptor-G complex in a conformation stabilized by unique NPxxL motif.

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Current and future strategies for targeting the endothelin pathway in cardiovascular disease.

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Sovateltide (ILR-1620) Improves Motor Function and Reduces Hyperalgesia in a Rat Model of Spinal Cord Injury.

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Advances in Therapies to Treat Neonatal Hypoxic-Ischemic Encephalopathy.

Ranjan A, Gulati A J Clin Med. 2023; 12(20).

PMID: 37892791 PMC: 10607511. DOI: 10.3390/jcm12206653.

References

Davenport A, Hyndman K, Dhaun N, Southan C, Kohan D, Pollock J . Endothelin. Pharmacol Rev. 2016; 68(2):357-418. PMC: 4815360. DOI: 10.1124/pr.115.011833. View

Puppala B, Awan I, Briyal S, Mbachu O, Leonard M, Gulati A . Ontogeny of endothelin receptors in the brain, heart, and kidneys of neonatal rats. Brain Dev. 2014; 37(2):206-15. DOI: 10.1016/j.braindev.2014.04.008. View

Ehrenreich H, Nau T, Dembowski C, Hasselblatt M, Barth M, Hahn A . Endothelin b receptor deficiency is associated with an increased rate of neuronal apoptosis in the dentate gyrus. Neuroscience. 2000; 95(4):993-1001. DOI: 10.1016/s0306-4522(99)00507-2. View

Alexander G, Knopman D, Emerson S, Ovbiagele B, Kryscio R, Perlmutter J . Revisiting FDA Approval of Aducanumab. N Engl J Med. 2021; 385(9):769-771. PMC: 11694499. DOI: 10.1056/NEJMp2110468. View

Palmer J, Baig S, Kehoe P, Love S . Endothelin-converting enzyme-2 is increased in Alzheimer's disease and up-regulated by Abeta. Am J Pathol. 2009; 175(1):262-70. PMC: 2708812. DOI: 10.2353/ajpath.2009.081054. View

Bale G, Mitra S, De Roever I, Sokolska M, Price D, Bainbridge A . Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury. J Cereb Blood Flow Metab. 2018; 39(10):2035-2047. PMC: 6775592. DOI: 10.1177/0271678X18777928. View

Foord S, Bonner T, Neubig R, Rosser E, Pin J, Davenport A . International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev. 2005; 57(2):279-88. DOI: 10.1124/pr.57.2.5. View

Gulati A, Hornick M, Briyal S, Lavhale M . A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders. Physiol Res. 2018; 67(Suppl 1):S95-S113. DOI: 10.33549/physiolres.933859. View

. 2020 Alzheimer's disease facts and figures. Alzheimers Dement. 2020; . DOI: 10.1002/alz.12068. View

10.

Briyal S, Nguyen C, Leonard M, Gulati A . Stimulation of endothelin B receptors by IRL-1620 decreases the progression of Alzheimer's disease. Neuroscience. 2015; 301:1-11. DOI: 10.1016/j.neuroscience.2015.05.044. View

11.

Briyal S, Gulati A, Gupta Y . Effect of combination of endothelin receptor antagonist (TAK-044) and aspirin in middle cerebral artery occlusion model of acute ischemic stroke in rats. Methods Find Exp Clin Pharmacol. 2007; 29(4):257-63. DOI: 10.1358/mf.2007.29.4.1106409. View

12.

Bamford J, Sandercock P, Dennis M, Burn J, Warlow C . Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991; 337(8756):1521-6. DOI: 10.1016/0140-6736(91)93206-o. View

13.

Gulati A, Kumar A, Shahani B . Cardiovascular effects of centrally administered endothelin-1 and its relationship to changes in cerebral blood flow. Life Sci. 1996; 58(5):437-45. DOI: 10.1016/0024-3205(95)02309-7. View

14.

Paris D, Humphrey J, Quadros A, Patel N, Crescentini R, Crawford F . Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. Neurol Res. 2003; 25(6):642-51. DOI: 10.1179/016164103101201940. View

15.

Nishikawa K, Ayukawa K, Hara Y, Wada K, Aoki S . Endothelin/endothelin-B receptor signals regulate ventricle-directed interkinetic nuclear migration of cerebral cortical neural progenitors. Neurochem Int. 2010; 58(3):261-72. DOI: 10.1016/j.neuint.2010.11.013. View

16.

Ehrenreich H, Oldenburg J, Hasselblatt M, Herms J, Dembowski C, Loffler B . Endothelin B receptor-deficient rats as a subtraction model to study the cerebral endothelin system. Neuroscience. 1999; 91(3):1067-75. DOI: 10.1016/s0306-4522(98)00663-0. View

17.

Azzopardi D, Strohm B, Edwards A, Dyet L, Halliday H, Juszczak E . Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009; 361(14):1349-58. DOI: 10.1056/NEJMoa0900854. View

18.

Yamashita K, Niwa M, Kataoka Y, Shigematsu K, Himeno A, Tsutsumi K . Microglia with an endothelin ETB receptor aggregate in rat hippocampus CA1 subfields following transient forebrain ischemia. J Neurochem. 1994; 63(3):1042-51. DOI: 10.1046/j.1471-4159.1994.63031042.x. View

19.

Cruz-Cruz C, Martinez-Nunez J, Perez M, Kravzov-Jinich J, Rios-Castaneda C, Altagracia-Martinez M . Evaluation of the Stroke-Specific Quality-of-Life (SSQOL) Scale in Mexico: A Preliminary Approach. Value Health Reg Issues. 2018; 2(3):392-397. DOI: 10.1016/j.vhri.2013.04.002. View

20.

Casey P, GILMAN A . G protein involvement in receptor-effector coupling. J Biol Chem. 1988; 263(6):2577-80. View