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Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium channel Kv1.5.

ABSTRACT: Three new aplysiatoxins, neo-debromoaplysiatoxin D (1), oscillatoxin E (2) and oscillatoxin F (3), accompanied by four known analogues (4-7), were identified from the marine cyanobacterium Lyngbya sp. Structural frames differ amongst these metabolites, and therefore we classified compounds 1 and 4-6 as aplysiatoxins as they possess 6/12/6 and 6/10/6 tricyclic ring systems featuring a macrolactone ring, and compounds 2, 3 and 7 as oscillatoxins that feature a hexane-tetrahydropyran in a spirobicyclic system. Bioactivity experiments showed that compounds 1 and 4-6 presented significant expression of phosphor-PKCδ whereas compounds 2, 5 and 7 showed the most potent blocking activity against potassium channel Kv1.5 with IC₅₀ values of 0.79 ± 0.032 μM, 1.28 ± 0.080 μM and 1.47 ± 0.138 μM, respectively. Molecular docking analysis supplementing the binding interaction of oscillatoxin E (2) and oscillatoxin F (3) with Kv1.5 showed oscillatoxin E (2) with a strong binding affinity of -37.645 kcal mol^-1 and oscillatoxin F (3) with a weaker affinity of -32.217 kcal mol^-1, further supporting the experimental data.

SUBMITTER: Tang YH

PROVIDER: S-EPMC9061199 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium channel Kv1.5.

Tang Yang-Hua YH Wu Jing J Fan Ting-Ting TT Zhang Hui-Hui HH Gong Xiao-Xia XX Cao Zheng-Yu ZY Zhang Jian J Lin Hou-Wen HW Han Bing-Nan BN

RSC advances 20190306 14

Three new aplysiatoxins, neo-debromoaplysiatoxin D (1), oscillatoxin E (2) and oscillatoxin F (3), accompanied by four known analogues (4-7), were identified from the marine cyanobacterium <i>Lyngbya</i> sp. Structural frames differ amongst these metabolites, and therefore we classified compounds 1 and 4-6 as aplysiatoxins as they possess 6/12/6 and 6/10/6 tricyclic ring systems featuring a macrolactone ring, and compounds 2, 3 and 7 as oscillatoxins that feature a hexane-tetrahydropyran in a sp ...[more]

PMID: 35521179

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Project description:Kv1.5 (KCNA5) is expressed in the heart, where it underlies the I(Kur) current that controls atrial repolarization, and in the pulmonary vasculature, where it regulates vessel contractility in response to changes in oxygen tension. Atrial fibrillation and hypoxic pulmonary hypertension are characterized by downregulation of Kv1.5 protein expression, as well as with oxidative stress. Formation of sulfenic acid on cysteine residues of proteins is an important, dynamic mechanism for protein regulation under oxidative stress. Kv1.5 is widely reported to be redox-sensitive, and the channel possesses 6 potentially redox-sensitive intracellular cysteines. We therefore hypothesized that sulfenic acid modification of the channel itself may regulate Kv1.5 in response to oxidative stress.To investigate how oxidative stress, via redox-sensitive modification of the channel with sulfenic acid, regulates trafficking and expression of Kv1.5.Labeling studies with the sulfenic acid-specific probe DAz and horseradish peroxidase-streptavidin Western blotting demonstrated a global increase in sulfenic acid-modified proteins in human patients with atrial fibrillation, as well as sulfenic acid modification to Kv1.5 in the heart. Further studies showed that Kv1.5 is modified with sulfenic acid on a single COOH-terminal cysteine (C581), and the level of sulfenic acid increases in response to oxidant exposure. Using live-cell immunofluorescence and whole-cell voltage-clamping, we found that modification of this cysteine is necessary and sufficient to reduce channel surface expression, promote its internalization, and block channel recycling back to the cell surface. Moreover, Western blotting demonstrated that sulfenic acid modification is a trigger for channel degradation under prolonged oxidative stress.Sulfenic acid modification to proteins, which is elevated in diseased human heart, regulates Kv1.5 channel surface expression and stability under oxidative stress and diverts channel from a recycling pathway to degradation. This provides a molecular mechanism linking oxidative stress and downregulation of channel expression observed in cardiovascular diseases.

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Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium channel Kv1.5.

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Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium channel Kv1.5.

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