Glycosidic scaffold bearing multiple galloyl moieties from pomegranate disrupts transthyretin amyloids

Asuka Kagami; Nami Hashimoto; Ryoko Sasaki; Yutaro Fukushima; Hari Prasad Devkota; Shoya Tanaka; Mikiyo Wada; Kunitoshi Yamanaka; Shiori Yamakawa; Shogo Misumi; Takeshi Yokoyama; Mineyuki Mizuguchi; Takashi Sato; Teruya Nakamura; Shunsuke Kotani; Mary Ann Suico; Hirofumi Kai; Mitsuharu Ueda; Tsuyoshi Shuto

doi:10.1016/j.isci.2025.114170

Glycosidic scaffold bearing multiple galloyl moieties from pomegranate disrupts transthyretin amyloids

iScience. 2025 Nov 21;29(1):114170. doi: 10.1016/j.isci.2025.114170. eCollection 2026 Jan 16.

Authors

Asuka Kagami^{1

2}, Nami Hashimoto¹, Ryoko Sasaki¹, Yutaro Fukushima^{1

3}, Hari Prasad Devkota^{4

5}, Shoya Tanaka⁴, Mikiyo Wada⁴, Kunitoshi Yamanaka⁶, Shiori Yamakawa⁷, Shogo Misumi^{8

9}, Takeshi Yokoyama¹⁰, Mineyuki Mizuguchi¹⁰, Takashi Sato¹¹, Teruya Nakamura¹², Shunsuke Kotani⁴, Mary Ann Suico^{1

9}, Hirofumi Kai^{1

9}, Mitsuharu Ueda⁷, Tsuyoshi Shuto^{1

9}

Affiliations

¹ Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
² Program for Fostering Innovators to Lead a Better Co-being Society, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 862-8555, Japan.
³ Health Life Science S-HIGO Professional Fellowship Program, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 862-8555, Japan.
⁴ Department of Instrumental Analysis, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
⁵ Faculty of Humanities and Social Sciences, Kumamoto University, 2-40-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan.
⁶ Department of Molecular Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
⁷ Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
⁸ Department of Environmental and Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
⁹ Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
¹⁰ Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
¹¹ Department of Analytical and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
¹² Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.

Abstract

Transthyretin (TTR) amyloidosis involves TTR misfolding and aggregation, causing systemic organ dysfunction. Current therapies stabilize TTR tetramers or reduce TTR production but are less effective against existing amyloid deposits. Here, we identified 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), derived from pomegranate (Punica granatum L.) leaf-and-branch extracts (PGL), as a disruptor of preformed TTR amyloid fibrils. PGG disaggregated fibrils formed by V30M and wild-type (WT) TTR, which are linked to hereditary Transthyretin Amyloidosis (ATTR) (ATTRv) and ATTRwt, respectively. Structure-activity relationship studies showed galloyl moieties are essential. In Caenorhabditis elegans-expressing human TTR_81-127, PGG reduced TTR aggregation and extended both lifespan and healthspan. PGG selectively targeted TTR amyloids without affecting amyloid-β fibrils, indicating specificity. PGG disrupted TTR amyloid fibrils isolated from patient cardiac tissue. These findings suggest that PGG shows therapeutic potential for TTR amyloidosis by directly targeting and disrupting pathogenic amyloid aggregates.

Keywords: Biological sciences; Health sciences; Natural product biochemistry; Natural product chemistry.