Tokyo University of Science


2022.02.09 Wednesday

Novel Synthetic Process for the Core Structure of the Fungal Antiviral Agent Neoechinulin B and Its Derivatives

Tokyo University of Science
National Institute of Infectious Diseases
Azabu University
Ochanomizu University

Scientists propose a two-step synthesis process for anti-viral compounds neoechinulin B and its derivatives

The fungus-derived compound neoechinulin B demonstrates promising antiviral activity. To realize its potential as an antiviral agent, however, a viable method for preparing more potent derivatives synthetically is necessary. In a recent breakthrough, scientists from Japan designed a simple route for synthesizing neoechinulin B and its derivatives under mild laboratory conditions. Neoechinulin B and six derivatives exhibited excellent antiviral activities against Hepatitis C virus and SARS-CoV-2, the virus responsible for the COVID-19 pandemic.

Novel Synthetic Process for the Core Structure of the Fungal Antiviral Agent Neoechinulin B and Its Derivatives

The solutions to many of humanity's problems can be found within nature. For instance, who could have guessed that an antibiotic as powerful as penicillin would be found in a common mold, or that the drug aspirin would be derived from the bark of the willow tree?

Research into natural products has become a crucial part of drug discovery. Natural products have exhibited promising specificity and efficacy when used against a variety of pathogens, including viruses. For instance, an organic compound called neoechinulin B, isolated from the fungus Eurotium rubrum, has demonstrated antiviral activity against hepatitis C virus (HCV). However, the isolation of such compounds from natural sources can get quite tedious and expensive. Yet, the attempts to synthetically synthesize it seem to be very scarce.

Thus, a group of scientists from across Japan rose to the occasion and embarked on a mission: To discover a simple route for synthesizing neoechinulin B under laboratory conditions. The team included Prof. Kouji Kuramochi and Dr. Koichi Watashi from Tokyo University of Science, along with Dr. Hirofumi Ohashi, Dr. Shusuke Tomoshige, Dr. Kenji Ohgane, and Dr. Shinji Kamisuki from the National Institute of Infectious Diseases, Tohoku University, Ochanomizu University, and Azabu University, respectively. Their findings were recently published in the Journal of Natural Products.

Commenting on their strategy, Prof. Kuramochi, the lead author of the study, says: "We designed a streamlined two-step synthesis strategy to obtain diketopiperazine scaffold of neoechinulin B. The process involved the base-induced coupling of available piperazine-2,5-dione derivative was aldehydes. The coupled products were then treated with a commercial reagent called tetra-n-butylammonium fluoride (TBAF) which gave us neoechinulin B and its 16 other derivatives."

To ascertain the efficacy of their products, the team tested the antiviral activity of neoechinulin B and its derivatives against different positive-strand RNA viruses, such as HCV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They found that some derivatives showed anti-HCV activity with minimal cell toxicity, while others showed anti-SARS-CoV-2. Moreover, six derivatives exhibited both strong anti-HCV and SARS-CoV-2.

Further studies by the research team uncovered that neoechinulin B and one derivative can reduced the transcriptional activity of liver X receptors (LXRs). This subsequently disrupts the formation of double-membrane vesicles (DMV), which are the sites where viral RNA replication occur. This process results in reduced viral replication in the infected cells.

Along with the 17 active compounds, the scientists also produced three other compounds which, while structurally related to the others, possessed none of the antiviral properties. Further investigation into their molecular structure revealed that inactive compounds were missing the exomethylene moiety which is the key to the antiviral activities of neoechinulin B and its 16 derivatives against HCV and SARS-CoV-2.

The team believes that the insights from this research could be used as a framework for the development of new broad-spectrum antiviral drugs. The study also solidifies the fact that natural products can act as promising lead compounds for the development of antiviral drugs."The skeleton of neoechinulin B is simple, but only one chemical synthesis method has been reported in the past. Our research presented a simple and viable method for obtaining promising antiviral compounds bringing us one step closer to its practical application," concludes Prof. Kuramochi.

Authors  : Kota Nishiuchi1, Hirofumi Ohashi1,2,3, Kazane Nishioka1,2, Masako Yamasaki1,2, Masateru Furuta1, Takumi Mashiko1, Shusuke Tomoshige1,4, Kenji Ohgane1,5, Shinji Kamisuki6, Koichi Watashi1,2,3, and Kouji Kuramochi1
Title of original paper  : Synthesis and Antiviral Activities of Neoechinulin B and Its Derivatives
Journal  : Journal of Natural Products
DOI  : 10.1021/acs.jnatprod.1c01120
Affiliations  : 1Department of Applied Biological Science, Tokyo University of Science, Japan.
2Department of Virology II, National Institute of Infectious Diseases, Japan.
3Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Japan.
4Graduate School of Life Sciences, Tohoku University, Japan.
5Department of Chemistry, Ochanomizu University, Japan.
6School of Veterinary Medicine and Center for Human and Animal Symbiosis Science, Azabu University, Japan.
Further Information

Professor Kouji Kuramochi
Department of Applied Biological Science
Tokyo University of Science
Email: kuramoch【@】

Koichi Watashi (Director)
Research Center for Drug and Vaccine Development
National Institute of Infectious Diseases
Email: kwatashi【@】

Associate Professor Shinji Kamisuki
School of Veterinary Medicine and Center for Human and Animal Symbiosis Science
Azabu University
Email: kamisuki【@】

Dr Kenji Ohgane
Department of Chemistry
Ochanomizu University
Email: ohgane.kenji【@】

Media contact

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Public Relations Divisions
Tokyo University of Science
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Business Operation Division
National Institute of Infectious Diseases
Email: info【@】

Kimiyoshi Arishima
Public Relations Divisions, Azabu University
Email: koho【@】

Daisuke Takatori
Planning and Strategy Division, Public Relations Unit, Ochanomizu University
Email: info【@】

About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of "Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

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About Professor Kouji Kuramochi from Tokyo University of Science

Funding information

This study was supported by Program for Basic and Clinical Research on Hepatitis (JP20fk0210036) and Research Program on Emerging and Re-emerging Infectious Diseases (JP20fk0108411 and JP20fk0108511) from the Japan Agency for Medical Research and Development (AMED). This work was also supported by Smoking Research Foundation and Japan Society for the Promotion of Science KAKENHI (20H03499). In addition, this work was supported by an on-campus grant in TUS, funded by a donation from "Account for Donations to Develop Vaccine and Medicine to Treat COVID-19", which was established by Sumitomo Mitsui Trust Bank, Limited.


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