Hisaaki Hirose

Program-Specific Associate Professor, Institute for Chemical Research, Kyoto University *Profile is at the time of the award.

2023Inamori Research GrantsBiology & Life sciences

Research topics
Elucidation of the cell selectivity mechanism of the antibody cytosolic delivery peptide
Keyword
Summary
Antibody drugs are promising therapeutics for many diseases, but their targets have been limited to extracellular molecules due to their low permeability through cell membranes. The development of simple and feasible methods to deliver antibodies into cells will lead to an expansion of drug targets.
The L17E peptide can easily deliver macromolecules, including antibodies, into living cells. However, the details of how the peptide interacts with the cell membrane and delivers macromolecules remain unclear. I will elucidate the molecular basis of L17E-based intracellular delivery to develop a more effective method for intracellular delivery of antibodies.

Comment

I am grateful to the Inamori Foundation and the reviewers for this prestigious research grant. I will elucidate and understand the mechanisms of cellular functions and designed molecules so that my research can bridge between basic and applied research as well as between chemistry and cell biology.

Outline of Research Achievments

In our laboratory, we developed the L17E peptide, which facilitates the delivery of biomacromolecules, including antibodies, into the cytosol. However, its precise mechanism of cargo transport remained unclear. In this study, we focused on the observation that the delivery efficiency of L17E differs among various cell types. We performed a comprehensive search for genes critical to L17E function and conducted further analyses. Our findings identified KCNN4 as an essential gene for L17E-mediated cytosolic delivery, specifically highlighting the importance of the calcium-activated potassium channel KCa3.1 encoded by KCNN4. Based on this elucidated molecular basis, we anticipate that further development of high-efficiency antibody delivery technologies targeting specific cells will be possible in the future.


Kuriyama, M., Hirose, H.* et al. (2025) “KCNN4 as a genomic determinant of cytosolic delivery by the attenuated cationic lytic peptide L17E” Mol Ther doi: 10.1016/j.ymthe.2024.12.050.


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Biology & Life sciences