Poster Presentation The 16th Australian Peptide Conference 2025

Photoswitchable peptidic modulators of Acid-Sensing Ion Channels (#139)

Nataliia Petlovana 1 , Sergii Afonin 1 , Marcel Huhn 1 , Iryna Semchuk 2 , Illia Hutskalov 1 , Fabian Hoffman 1 , Oleg Babii 1 , Igor V Komarov 3 , Anne S Ulrich 1
  1. Karlsruhe Institute of Technology, Karlsruhe, Germany
  2. National Cancer Institute of Ukraine, Kyiv, Ukraine
  3. Taras Shevchenko University of Kyiv, Kyiv, Ukraine

Photopharmacology [1] has recently emerged as a promising strategy offering enhanced target selectivity, reduced off-target effects, and minimised systemic toxicity. The main scope of this work is the development of photocontrollable peptidic modulators of ASICs and the demonstration of their light-dependent activity in vitro and in vivo.

ASICs are voltage-independent, proton-gated cation channels permeable to Na+ and widely expressed throughout the central and peripheral nervous systems. ASICs play vital roles in the pain perception, synaptic plasticity, learning, memory, and neuronal degeneration; they are crucial regulators in conditions associated with necrotic tissue acidosis.

The photocontrollable peptidic ASIC modulators we design here are diarylethene (DAE)-modified cyclic beta-hairpins, similar to previously developed gramicidin S-based photoswitchable membranolytic peptides [2,3]. As a functional prototype, we explore ASIC-binding fragments of mambalgin-1 (three-finger peptide toxin, from the venom of Dendroaspis polylepis, analge, exhibiting strong analgesic effects with in vitro IC50=10±1 nM) and psalmotoxin-1 (disulfide-rich 40-mer peptide toxin, from the venom of Psalmopoeus cambridgei, the only known selective inhibitor of ASIC1a with IC50=0.44 nM).

The development strategy involves the synthesis of three types of libraries: one of non-photoswitchable derivatives based on known toxin interaction motifs and DAE building block surrogates, and their respective photocontrolled analogues with the DAE photoswitch, incorporated either into the backbone or via the side-chains.

The peptides are then being characterised for their structure and conformational plasticity (circular dichroism spectroscopy in variable environments); for their in vitro bioactivity: cytotoxicity (colorimetric cell death assays), modulation of the ASIC activity (“patch-clamp” measurements, fluorescence spectroscopy-based Ca2+-influx assay) and for the kinetics and efficiency of photoactivation.

This work aims to yield potent and safe photocontrolled peptide ASIC modulators (i.e. finding the derivative with the most significant efficacy differences between DAE photoisomers) with potential applications in the treatment of pain, central neurological diseases, and other pathological conditions involving ASIC dysregulation.

  1. Liu Y, Wang T, Wang W. Chem Soc Rev. 2025, 54:5792. doi: 10.1039/d5cs00125k.
  2. Babii O, et al. J Med Chem. 2018, 61:10793. doi: 10.1021/acs.jmedchem.8b01428.
  3. Horbatok K, et al. RSC Med Chem. 2025, in press. doi: 10.1039/d5md00075k.