ArticleThe Journal of general physiology2021
HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD-ligand interactions.
Article in The Journal of general physiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Modulators of the Human Voltage-Gated Proton Channel HPharmaceuticals (Basel, Switzerland) · 2025Review
- Hv1 channel in immune cells and pharmacology.Pharmacological research · 2025Review
- Genetic Code Expansion for Mechanistic Studies in Ion Channels: An (Un)natural Union of Chemistry and Biology.Chemical reviews · 2024Review
- Identification of a Novel Structural Class of HJournal of chemical information and modeling · 2024Article
- Role of S100 and YKL40 on Intraventricular Cerebral Hemorrhages in the Preterm Infant and the Neuroprotective Role of miR-138- siRNAs-HIF-1a and miR-21-siRNAs-HVCN1 in Neonatal Mice with Nerve Injury.Current medicinal chemistry · 2024Article
- Inhibition of the HFrontiers in immunology · 2024Article
- Trapping Charge Mechanism in Hv1 Channels (International journal of molecular sciences · 2023Article
- Mechanically-primed voltage-gated proton channels from angiosperm plants.Nature communications · 2023Article
- 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HPharmaceuticals (Basel, Switzerland) · 2023Article
- Microglial reprogramming by Hv1 antagonism protects neurons from inflammatory and glutamate toxicity.Journal of neurochemistry · 2023Article
- The role of macrophage ion channels in the progression of atherosclerosis.Frontiers in immunology · 2023Review
- Role of voltage-gated proton channel (Hv1) in cancer biology.Frontiers in pharmacology · 2023Review
- The role of Phe150 in human voltage-gated proton channel.iScience · 2022Article
- RNA-Seq Analyses Reveal Roles of the HVCN1 Proton Channel in Cardiac pH Homeostasis.Frontiers in cell and developmental biology · 2022Article
- Effects of Mexiletine on a Race-specific Mutation in NaFrontiers in physiology · 2022Article
- A novel Hv1 inhibitor reveals a new mechanism of inhibition of a voltage-sensing domain.The Journal of general physiology · 2021Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The human voltage-gated proton channel Hv1 is a drug target for cancer, ischemic stroke, and neuroinflammation. It resides on the plasma membrane and endocytic compartments of a variety of cell types, where it mediates outward proton movement and regulates the activity of NOX enzymes. Its voltage-sensing domain (VSD) contains a gated and proton-selective conduction pathway, which can be blocked by aromatic guanidine derivatives such as 2-guanidinobenzimidazole (2GBI). Mutation of Hv1 residue F150 to alanine (F150A) was previously found to increase 2GBI apparent binding affinity more than two orders of magnitude. Here, we explore the contribution of aromatic interactions between the inhibitor and the channel in the presence and absence of the F150A mutation, using a combination of electrophysiological recordings, classic mutagenesis, and site-specific incorporation of fluorinated phenylalanines via nonsense suppression methodology. Our data suggest that the increase in apparent binding affinity is due to a rearrangement of the binding site allowed by the smaller residue at position 150. We used this information to design new arginine mimics with improved affinity for the nonrearranged binding site of the wild-type channel. The new compounds, named "Hv1 Inhibitor Flexibles" (HIFs), consist of two "prongs," an aminoimidazole ring, and an aromatic group connected by extended flexible linkers. Some HIF compounds display inhibitory properties that are superior to those of 2GBI, thus providing a promising scaffold for further development of high-affinity Hv1 inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.