Potential Therapeutic Applications of Synthetic Conotoxin s-cal14.2b, Derived from Californiconus californicus, for Treating Type 2 Diabetes

Abstract

The FDA’s approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or ligands alter normal physiological functions, as in metabolic diseases such as Type 2 diabetes. In this study, the synthetic cal14.2b (s-cal14.2b) from the unusual Californiconus californicus demonstrated bioactivity on NIT-1 insulinoma cell lines stimulating insulin secretion detecting by high performance liquid chromatography (HPLC). Accordingly, s-cal14.2b increased the CaV1.2/1.3 channel-current by 35 ± 4% with a recovery τ of 10.3 ± 4 s in primary cell culture of rat pancreatic β-cells. The in vivo results indicated a similar effect of insulin secretion on mice in the glucose tolerance curve model by reducing the glucose from 500 mg/dL to 106 mg/dL in 60 min, compared to the negative control of 325 mg/dL at the same time. The PET-SCAN with radiolabeling 99mTc-s-cal14.2b demonstrated biodistribution and accumulation in rat pancreas with complete depuration in 24 h. These findings show the potential therapeutic use of s-cal14.2b in endocrinal pathologies such as early stages of Type 2 Diabetes where the pancreas’s capability to produce insulin is still effective.

Marine natural products

“…661 A 26-residue conotoxin belonging to the A-superfamily, identified from a cDNA library of C. striatus , exhibits in vivo analgesic activity, 662 while synthetic cal14.2b ( Californiconus californicus ) exhibited insulinotropic activities in vitro and in vivo suggesting potential roles in the treatment of Type 2 diabetes. 663 ω-Conotoxins characteristically inhibit N -type voltage-gated calcium channels and in the specific case of ω-conotoxin MVIIA, have application in the treatment of neuropathic pain. A new example, ω-conotoxin Bu8 ( C. bullatus ) is twice as active in vitro as MVIIA, is potently active in in vivo models and based upon NMR structure analysis and SAR of mutants and Bu8/MVIIA hybrids, exhibits a different target binding mode vs .…”

“…while synthetic cal14.2b (Californiconus californicus) exhibited insulinotropic activities in This journal is © The Royal Society of Chemistry 2023Natural Product Reports Reviewvitro and in vivo suggesting potential roles in the treatment of Type 2 diabetes 663. u-Conotoxins characteristically inhibit Ntype voltage-gated calcium channels and in the specic case of u-conotoxin MVIIA, have application in the treatment of neuropathic pain.…”

High-Throughput Prediction and Design of Novel Conopeptides for Biomedical Research and Development

“…They are often ideal resources for development of new drugs to play important roles in neurobiological research [4]. Over the past few decades, they have been used for treatment of many human diseases such as chronic pain, Parkinson's disease, Alzheimer's disease, epilepsy, diabetes, and cancer [5][6][7][8][9][10]. The most famous ω-MVIIA, commercially named as Ziconotide, was approved by the US Food and Drug Administration (FDA) in 2004 to treat chronic pain [11].…”