Strother, J. A. | Search bioRxiv

bioRxiv2022

Anion efflux mediates transduction in hair cells of zebrafish lateral line

Hair cells are the principal sensory receptors of the vertebrate auditory system, and transduce sounds with mechanically-gated ion channels that permit cations to flow from the surrounding endolymph into the cells. The lateral line of zebrafish has served as a key model system for understanding hair cell physiology and development, and it has often been speculated that these hair cells employ a similar transduction mechanism. In this study, we demonstrate that the hair cells are exposed to an unregulated external environment with cation concentrations that are too low to support transduction. Instead, our results indicate that hair cell excitation is mediated by a fundamentally different mechanism involving the outward flow of anions.

neuroscience↗

bioRxiv2019

Biological Evaluation of Molecules of the azaBINOL Class as Antiviral Agents: Specific Inhibition of HIV-1 RNase H Activity by 7-Isopropoxy-8-(naphth-1-yl)quinoline

Inspired by bioactive biaryl-containing natural products found in plants and the marine environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs in a singleround infectivity assay resulted in the identification of three promising antiviral compounds, including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOL B#24), which exhibited low-micromolar activity. The active compounds and several close structural analogues were further tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus replication system (EASY-HIT). Mode-of-action studies using a time-of-addition assay indicated that azaBINOL B#24 acts after viral entry but before viral assembly and budding. HIV-1 reverse transcriptase (RT) assays that individually test for polymerase and RNase H activity were used to demonstrate that B#24 inhibits RNase H activity, most likely allosterically. Further binding analysis using bio-layer interferometry (BLI) showed that B#24 interacts with HIV-1 RT in a highly specific manner. These results indicate that azaBINOL B#24 is a potentially viable, novel lead for the development of new HIV-1 RNase H inhibitors. Furthermore, this study demonstrates that the survey of libraries of synthetic compounds, designed purely with the goal of facilitating chemical synthesis in mind, may yield unexpected and selective drug leads for the development of new antiviral agents.

pharmacology and toxicology↗