Abstract
α-Conotoxin TxIB specifically blocked α6/α3β2β3 acetylcholine receptors (nAChRs), and it could be a potential probe for studying addiction and other diseases related to α6/α3β2β3 nAChRs. However, as a peptide, TxIB may suffer from low stability, short half-life, and poor bioavailability. In this study, cyclization of TxIB was used to improve its stability. Four cyclic mutants of TxIB (cTxIB) were synthesized, and the inhibition of these analogues on α6/α3β2β3 nAChRs as well as their stability in human serum were measured. All cyclized analogues had similar activity compared to wild-type TxIB, which indicated that backbone cyclization of TxIB had no significant effect on its activity. Cyclization of TxIB with a seven-residue linker improved its stability significantly in human serum. Besides this, the results showed that cyclization maintained the activity of α-conotoxin TxIB, which is conducive to its future application.
Highlights
Nicotine acetylcholine receptors are ligand-gated ion channels, which are key targets for the treatment of depression, addiction, Parkinson’s disease, neuralgia, Alzheimer’s disease, and cancer [1,2,3,4,5]. α6/α3β2β3 (α6β2*) nAChRs are highly expressed in the region of midbrain dopamine (DA) neurons in the central nervous system, which regulates the release of dopamine [6]
The test results displayed that the effect of cyclization in 3 h was better than that in 6 h
Discussion α6β2* nAChRs regulate the release of dopamine and are important targets associated with a few neuropsychiatric diseases, including Parkinson’s disease and nicotine addiction [6]
Summary
Nicotine acetylcholine receptors (nAChRs) are ligand-gated ion channels, which are key targets for the treatment of depression, addiction, Parkinson’s disease, neuralgia, Alzheimer’s disease, and cancer [1,2,3,4,5]. α6/α3β2β3 (α6β2*) nAChRs are highly expressed in the region of midbrain dopamine (DA) neurons in the central nervous system, which regulates the release of dopamine [6]. Several chemical modifications have been approached to ameliorate the metabolic stability of conotoxins, including cyclization, disulfide bond engineering, residue substitutions, N-terminal acetylation, glycosylation, PEGylation, etc. GeXIVA, have been successfully cyclized, and their stability has been improved to varying degrees serum while preserving biological activity for rat α6β2* According to these studies, cyclic conotoxins were regulated by the properties of the linkerfour TxIB analogues sequences, including the length and amino acid composition [39]. An appropriate linker length were redesigned with four to seven residues in the linker region based on the distance between the contributes to preservation of the original structure of conotoxins, while the amino acid composition may affect(Figure their activities.
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