Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders

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.

Cryo-EM structure of the endothelin-1-ETB-Gi complex

“…The development of ET B agonists is also underway, as they provide therapeutic benefits such as vasodilation and neuroprotection Davenport et al, 2016 ; Koyama, 2021 . IRL1620, a truncated analog of ET-1, is the smallest ET B -selective agonist that has been shown to selectively and transiently increase tumor blood flow Gulati et al, 2012 , making it a potential adjuvant cancer therapy for enhancing the delivery of anti-tumor drugs and acute ischemic stroke Ranjan and Gulati, 2022 . However, IRL1620 is a linear peptide with exposed N- and C-termini and thus has problems in terms of pharmacokinetics and drug delivery.…”

Characterization of age- and stage-dependent impaired adult subventricular neurogenesis in 5XFAD mouse model of Alzheimer’s disease

“…Secondly, strategies that rescue impaired neurogenesis have the potential to ameliorate cognitive dysfunction as AD progresses ( 9 , 34 , 35 ). For this reason, the development of therapeutics to treat AD by increasing neurogenesis, which is impaired in AD, is underway ( 36 , 37 ), but it is unclear at which stage of AD a drug intervention should be applied for the most effective clinical benefit. Therefore, it is important to identify impairment of adult SVZ neurogenesis as AD progresses, as this may play an important role in determining the timing of administration of AD therapeutics that increase neurogenesis.…”

Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification

“…Sovateltide is an endothelin-B receptor agonist that promotes the differentiation of neuronal progenitors to produce mature neuronal cells and exhibits antioxidant, anti-apoptotic, and mitochondrial functional enhancement properties [ 87 ].…”