Towards VDAC pharmacology: Developing small-peptide channel inhibitors inspired by nature
Abstract
The Voltage-Dependent Anion Channel (VDAC) forms a unique pathway across the mitochondrial outer membrane for small ions and water-soluble metabolites, such as ATP and ADP. Despite VDAC's involvement in both normal regulation of respiration and in a wide variety of mitochondria-associated pathologies, there are, surprisingly, no known FDA-approved pharmacological agents targeting VDAC. Earlier, we have shown that VDAC can be regulated through its interactions with well-known cytosolic proteins--dimeric tubulin and -synuclein (Syn)--that are able to reversibly block this channel at nanomolar concentrations. We hypothesized that the architecture of a prospective VDAC inhibitor should fulfill two main requirements: possess a negatively charged disordered polypeptide C- or N-terminus as a pore blocking domain and feature a mitochondrial membrane-binding domain. Using Syn as a template, we engineered three peptides and demonstrated that they all characteristically block VDAC reconstituted into planar lipid membranes in a controllable manner, thereby mimicking the actions of tubulin and Syn. The VDAC blockage times induced by the synthetic peptides are comparable to Syn-induced blockages, though the half-effect solution concentration for synthetic blockers is a hundred times higher than that of Syn. Our work can be considered a proof-of-principle study that informs future development of mitochondria-targeting pharmacological tools.
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BibTeX
@misc{rostovtseva2026towards,
title = {{Towards VDAC pharmacology: Developing small-peptide channel inhibitors inspired by nature}},
author = {Tatiana K. Rostovtseva and Philip A. Gurnev and David P. Hoogerheide and Sergey M. Bezrukov},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758907},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758907v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Towards VDAC pharmacology: Developing small-peptide channel inhibitors inspired by nature
AU - Tatiana K. Rostovtseva
AU - Philip A. Gurnev
AU - David P. Hoogerheide
AU - Sergey M. Bezrukov
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758907
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758907v1
AB - The Voltage-Dependent Anion Channel (VDAC) forms a unique pathway across the mitochondrial outer membrane for small ions and water-soluble metabolites, such as ATP and ADP. Despite VDAC's involvement in both normal regulation of respiration and in a wide variety of mitochondria-associated pathologies, there are, surprisingly, no known FDA-approved pharmacological agents targeting VDAC. Earlier, we have shown that VDAC can be regulated through its interactions with well-known cytosolic proteins--dimeric tubulin and -synuclein (Syn)--that are able to reversibly block this channel at nanomolar concentrations. We hypothesized that the architecture of a prospective VDAC inhibitor should fulfill two main requirements: possess a negatively charged disordered polypeptide C- or N-terminus as a pore blocking domain and feature a mitochondrial membrane-binding domain. Using Syn as a template, we engineered three peptides and demonstrated that they all characteristically block VDAC reconstituted into planar lipid membranes in a controllable manner, thereby mimicking the actions of tubulin and Syn. The VDAC blockage times induced by the synthetic peptides are comparable to Syn-induced blockages, though the half-effect solution concentration for synthetic blockers is a hundred times higher than that of Syn. Our work can be considered a proof-of-principle study that informs future development of mitochondria-targeting pharmacological tools.
SN - 2692-8205
ER -