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Structure-Activity Relationship Evaluation of Wasp Toxin ?-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels.

ABSTRACT: Beta-pompilidotoxin (?-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel Na_V1.1 with weak activity (40% activation at 3.3 ?M of ?-PMTX). Through rational design of ?-PMTX analogs, we have identified peptides with significantly improved activity on human Na_V1.1 (1170% activation at 3.3 ?M of peptide 18). The underlying structure-activity relationship suggests importance of charge interactions (from residue Lys-3) and lipophilic interactions (from residue Phe-7 and Ser-11). Three top-ranked analogs showed parallel activity improvement for other neuronal sodium channels (human Na_V1.2/1.3/1.6/1.7) but not muscular subtypes (Na_V1.4/1.5). Finally, we found that analog 16 could partially rescue the pharmacological block imposed by Na_V1.1/1.3 selective inhibitor ICA-121431 in cultured mouse cortical GABAergic neurons, demonstrating an activating effect of this peptide on native neuronal sodium channels and its potential utility as a neuropharmacological tool.

SUBMITTER: Garrison CE

PROVIDER: S-EPMC7074216 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Structure-Activity Relationship Evaluation of Wasp Toxin β-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels.

Garrison Catherine E CE Guan Wendy W Kato Mitsunori M Tamsett Thomas T Patel Tajesh T Sun Yishan Y Pathak Tejas P TP

ACS medicinal chemistry letters 20191025 3

Beta-pompilidotoxin (β-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel NaV1.1 with weak activity (40% activation at 3.3 μM of β-PMTX). Through rational design of β-PMTX analogs, we have identified peptides with significantly improved activity on human NaV1.1 (1170% activation at 3.3 μM of peptide 18). The underlying structure-activity relationship suggests importance of charge interactions (from residue Lys-3) and lipophilic i ...[more]

PMID: 32184969

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Project description:Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14(-/-) mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na(+) current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14(-/-) mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.-Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability.

Dataset Information

Structure-Activity Relationship Evaluation of Wasp Toxin ?-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels.

Publications

Structure-Activity Relationship Evaluation of Wasp Toxin β-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels.

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