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New Two-Step Process for Synthesising Neoechinulin B Paves the Way for Developing Anti-Viral Drugs

Researchers have identified six derivatives of Neoechinulin B that show strong anti-hepatitis C virus and anti-SARS-CoV-2 activities.

Known to cause liver inflammation, the hepatitis C virus is a bloodborne pathogen that can lead to acute or chronic hepatitis. While some people suffer mild, short-term illness, more than half of those infected suffer from long-term, chronic infection. At times, hepatitis C can result in critical, lifelong consequences such as liver cirrhosis and cancer. In 2019, the World Health Organization reported around 290,000 hepatitis C-related deaths, most of which were attributed to cirrhosis and hepatocellular carcinoma. Despite the availability of effective antiviral medicines, access to hepatitis C diagnosis and treatment are generally low. Moreover, symptoms of chronic hepatitis C are generally not apparent and only appear when liver disease has advanced.

In recent years, scientist have discovered an organic compound isolated from the fungus Eurotium rubrum, known as neoechinulin B, exhibits antiviral activity against the hepatitis C virus, making it an attractive therapeutic candidate. However, isolating these compounds from natural sources is not only costly but also tedious. Noticing that there have been limited attempts to synthetically synthesise neoechinulin B, a team of researchers from Japan were determined to discover a route for synthesising neoechinulin B under laboratory conditions, and have now developed a simple, two-step strategy of their own.

“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 [with] 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,” explained Professor Kuramochi, the lead author of the study.

To assess the efficacy of their products, Kuramochi and colleagues examined the antiviral activity of neoechinulin B and its derivatives against various positive-strand RNA viruses such as the hepatitis C virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Their experiments revealed that some derivatives displayed anti-hepatitis C virus activity with minimal cell toxicity, whereas others exhibited anti-SARS-CoV-2 activity. Overall, they successfully identified six derivatives that showed both strong anti-hepatitis C virus and anti-SARS-CoV-2 activities.

Through further evaluations, the researchers found that neoechinulin B and one particular derivative can reduce the transcriptional activity of liver X receptors (LXRs). As a result, the formation of double-membrane vesicles, where viral RNA replication occurs, is disrupted, effectively reducing viral replication in infected cells. In total, the scientists produced 17 active compounds, and three inactive ones. Despite being structurally related to the active compounds, the inactive compounds did not appear to possess any antiviral property. Upon analysing their molecular structure, the researchers discovered that the inactive compounds were lacking the exomethylene moiety found in active ones. This exomethylene moiety appears to be the key to the antiviral activities of neoechinulin B and its 16 derivatives against the hepatitis C virus and SARS-CoV-2.

With these encouraging results, the researchers believe that their study has offered new insights that could potentially be used as a framework to develop new broad-spectrum antiviral drugs. Currently, the team is working to better explain the underlying mechanisms of action of neoechinulin B and is conducting further structural optimisation to enhance the antiviral efficiency of neoechinulin B and its derivatives.

“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,” concluded Professor Kuramochi. [APBN]

Source: Nishiuchi et al. (2022). Synthesis and Antiviral Activities of Neoechinulin B and Its Derivatives. Journal of Natural Products, 85, 1, 284–291.