Epithelial Sodium Channel Inhibition by Amiloride Addressed with THz Spectroscopy and Molecular Modeling

Mernea, Maria; Ulăreanu, Roxana; Cucu, Dana; Al-Saedi, Jasim Hafedh; Pop, Cristian-Emilian; Fendrihan, Sergiu; Anghelescu, Giorgiana Diana Carmen; Mihăilescu, Dan

doi:10.3390/molecules27103271

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…Mutation at this position in all three subunits removes any sensitivity to amiloride blocking [75]. A recent study of the cryo-EM structure of hENaC [38,39] by THz spectroscopy, coupled with molecular modelling, confirms this as the amiloride binding site [76].…”

Section: Amiloride-binding Sitementioning

confidence: 76%

The Epithelial Sodium Channel—An Underestimated Drug Target

Lemmens‐Gruber

Tzotzos²

2023

IJMS

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Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.

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Section: Amiloride-binding Sitementioning

confidence: 76%

The Epithelial Sodium Channel—An Underestimated Drug Target

Lemmens‐Gruber

Tzotzos²

2023

IJMS

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“…In addition, the dynamical effects exerted by ligands can be accessed from simulation trajectories. Mernea et al combined terahertz (THz) spectroscopy and MD simulations and showed the binding site of an epithelial sodium channel blocker and reduced channel dynamics upon blocker binding . As more efforts poured into ion channel drug discovery from both experimental and computational approaches, the ligand-binding, modulation, mutations, and permeation pathway of ion channels will be further illuminated.…”

Section: Membrane Protein Simulationsmentioning

confidence: 99%

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications

Feng

Park

Choi

et al. 2023

J. Chem. Theory Comput.

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Molecular dynamics simulations of membranes and membrane proteins serve as computational microscopes, revealing coordinated events at the membrane interface. As G protein-coupled receptors, ion channels, transporters, and membrane-bound enzymes are important drug targets, understanding their drug binding and action mechanisms in a realistic membrane becomes critical. Advances in materials science and physical chemistry further demand an atomistic understanding of lipid domains and interactions between materials and membranes. Despite a wide range of membrane simulation studies, generating a complex membrane assembly remains challenging. Here, we review the capability of CHARMM-GUI Membrane Builder in the context of emerging research demands, as well as the application examples from the CHARMM-GUI user community, including membrane biophysics, membrane protein drugbinding and dynamics, protein−lipid interactions, and nano-bio interface. We also provide our perspective on future Membrane Builder development.

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“…The models of the Mamb-2 complex with the heterotrimeric α-ENaC/ASIC1a/γ-ENaC and homotrimeric ASIC1a channels were built in a lipid bilayer composed of palmitoyloleoylphosphatidylcholine (POPC) molecules similar to [41] using the CHARMM-GUI [42] Membrane Builder tool [43]. To represent N-glycans at sites 368/395 and 209/497 at the ASIC1a and γ-ENac subunits, respectively, a classic pentasaccharide core composed of two N-Acetylglucosamine (GlcNAc) and three Mannose (Man) residues was used.…”

Section: Modeling Of the Mambalgin-2 Complexes With The Asic1a And α-...mentioning

confidence: 99%

Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells

Lyukmanova,

Zaigraev,

Kulbatskii

et al. 2023

Toxins

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Cancer progression is characterized by microenvironmental acidification. Tumor cells adapt to low environmental pH by activating acid-sensing trimeric ion channels of the DEG/ENaC family. The α-ENaC/ASIC1a/γ-ENaC heterotrimeric channel is a tumor-specific acid-sensing channel, and its targeting can be considered a new strategy for cancer therapy. Mambalgin-2 from the Dendroaspis polylepis venom inhibits the α-ENaC/ASIC1a/γ-ENaC heterotrimer more effectively than the homotrimeric ASIC1a channel, initially proposed as the target of mambalgin-2. Although the molecular basis of such mambalgin selectivity remained unclear. Here, we built the models of the complexes of mambalgin-2 with the α-ENaC/ASIC1a/γ-ENaC and ASIC1a channels, performed MD and predicted the difference in the binding modes. The importance of the ‘head’ loop region of mambalgin-2 for the interaction with the hetero-, but not with the homotrimeric channel was confirmed by site-directed mutagenesis and electrophysiology. A new mode of allosteric regulation of the ENaC channels by linking the thumb domain of the ASIC1a subunit with the palm domain of the γ-ENaC subunit was proposed. The data obtained provide new insights into the regulation of various types of acid-sensing ion channels and the development of new strategies for cancer treatment.

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Epithelial Sodium Channel Inhibition by Amiloride Addressed with THz Spectroscopy and Molecular Modeling

Cited by 5 publications

References 48 publications

The Epithelial Sodium Channel—An Underestimated Drug Target

The Epithelial Sodium Channel—An Underestimated Drug Target

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications

Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells

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