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Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated with Alzheimer's Disease.
Angew Chem Int Ed Engl. 2020 12 14; 59(51):22994-22998.AC

Abstract

Rhizolutin (1) was discovered as a natural product of ginseng-rhizospheric Streptomyces sp. WON17. Its structure features an unprecedented 7/10/6-tricyclic dilactone carbon skeleton composed of dimethylcyclodecatriene flanked by a 7-membered and a 6-membered lactone ring based on spectroscopic analysis. During an unbiased screening of natural product libraries, this novel compound was found to dissociate amyloid-β (Aβ) plaques and tau tangles, which are key pathological hallmarks of Alzheimer's disease (AD). Rhizolutin treatment of APP/PS1 double transgenic mice with AD significantly dissociated hippocampal plaques. In vitro, rhizolutin substantially decreased Aβ-induced apoptosis and inflammation in neuronal and glial cells. Our findings introduce a unique chemical entity that targets Aβ and tau concurrently by mimicking misfolded protein clearance mechanisms of immunotherapy, which is prominently investigated in clinical trials.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Kwon Y
Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Shin J
Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
Nam K
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019, USA.
An JS
Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Yang SH
Department of Medical Biotechnology, Dongguk University, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea.
Hong SH
Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Bae M
Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Moon K
Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Cho Y
Research Animal Resource Center, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
Woo J
Research Animal Resource Center, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
Park K
Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), 679 Saimdang-ro, Gangneung-si, Gangwon-do, 25451, Republic of Korea.
Kim K
Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
Shin J
Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Kim BY
Microbiome Research Centre, ChunLab, Inc., 2477, JW Tower 6F, Nambusunhwan-ro, Seocho-gu, Seoul, 06725, Republic of Korea.
Kim Y
Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
Oh DC
Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsApoptosisInflammationMiceMice, TransgenicNeurogliaNeuronsNeuroprotective AgentsPlaque, AmyloidProtein AggregatesStreptomycestau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32844539

Citation

Kwon, Yun, et al. "Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated With Alzheimer's Disease." Angewandte Chemie (International Ed. in English), vol. 59, no. 51, 2020, pp. 22994-22998.
Kwon Y, Shin J, Nam K, et al. Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated with Alzheimer's Disease. Angew Chem Int Ed Engl. 2020;59(51):22994-22998.
Kwon, Y., Shin, J., Nam, K., An, J. S., Yang, S. H., Hong, S. H., Bae, M., Moon, K., Cho, Y., Woo, J., Park, K., Kim, K., Shin, J., Kim, B. Y., Kim, Y., & Oh, D. C. (2020). Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated with Alzheimer's Disease. Angewandte Chemie (International Ed. in English), 59(51), 22994-22998. https://doi.org/10.1002/anie.202009294
Kwon Y, et al. Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated With Alzheimer's Disease. Angew Chem Int Ed Engl. 2020 12 14;59(51):22994-22998. PubMed PMID: 32844539.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rhizolutin, a Novel 7/10/6-Tricyclic Dilactone, Dissociates Misfolded Protein Aggregates and Reduces Apoptosis/Inflammation Associated with Alzheimer's Disease. AU - Kwon,Yun, AU - Shin,Jisu, AU - Nam,Kwangho, AU - An,Joon Soo, AU - Yang,Seung-Hoon, AU - Hong,Seong-Heon, AU - Bae,Munhyung, AU - Moon,Kyuho, AU - Cho,Yakdol, AU - Woo,Jiwan, AU - Park,Keunwan, AU - Kim,Kyeonghwan, AU - Shin,Jongheon, AU - Kim,Byung-Yong, AU - Kim,YoungSoo, AU - Oh,Dong-Chan, Y1 - 2020/10/04/ PY - 2020/07/06/received PY - 2020/08/20/revised PY - 2020/8/28/pubmed PY - 2021/3/23/medline PY - 2020/8/27/entrez KW - Alzheimer's disease KW - amyloid β KW - lactones KW - natural products KW - tau protein SP - 22994 EP - 22998 JF - Angewandte Chemie (International ed. in English) JO - Angew Chem Int Ed Engl VL - 59 IS - 51 N2 - Rhizolutin (1) was discovered as a natural product of ginseng-rhizospheric Streptomyces sp. WON17. Its structure features an unprecedented 7/10/6-tricyclic dilactone carbon skeleton composed of dimethylcyclodecatriene flanked by a 7-membered and a 6-membered lactone ring based on spectroscopic analysis. During an unbiased screening of natural product libraries, this novel compound was found to dissociate amyloid-β (Aβ) plaques and tau tangles, which are key pathological hallmarks of Alzheimer's disease (AD). Rhizolutin treatment of APP/PS1 double transgenic mice with AD significantly dissociated hippocampal plaques. In vitro, rhizolutin substantially decreased Aβ-induced apoptosis and inflammation in neuronal and glial cells. Our findings introduce a unique chemical entity that targets Aβ and tau concurrently by mimicking misfolded protein clearance mechanisms of immunotherapy, which is prominently investigated in clinical trials. SN - 1521-3773 UR - https://www.unboundmedicine.com/medline/citation/32844539/Rhizolutin_a_Novel_7/10/6_Tricyclic_Dilactone_Dissociates_Misfolded_Protein_Aggregates_and_Reduces_Apoptosis/Inflammation_Associated_with_Alzheimer's_Disease_ DB - PRIME DP - Unbound Medicine ER -