What links Pho – the delicious Vietnamese noodle soup – and a billion-dollar blockbuster drug?
You may well recognise the sweet, liquorice-like flavour in your Pho noodle soup as coming from the star anise spice. But rewind to 2005, and your aromatic broth probably wasn’t so good. Frustrated Pho chefs couldn’t lay their hands on the traditional ingredient. Panic about a global flu pandemic was driving a gold rush for the star-shaped fruit.
Star anise has a long tradition in Chinese herbal medicine, and its extract has antiviral properties in its own right. But this wasn’t what drove the star anise bonanza.
Estimates that bird flu could kill millions had created sky-high demand for Tamiflu – Roche’s oral flu drug. To meet this demand, Roche needed huge amounts of shikimic acid, the key ingredient in Tamiflu production. The star anise shortage was caused by pharmaceutical companies stocking up on the fruit to extract its shikimic acid and sell it to Roche.
Tamiflu
Tamiflu (oseltamivir) is an oral antiviral drug developed by the pharmaceutical companies Gilead Sciences and Hoffmann-La Roche in the 1990s.
There is much we could discuss on Tamiflu, but here we’re going to keep our focus on star anise’s role in this notorious pharmaceutical.
The mechanism
Tamiflu works by targeting the neuraminidase enzyme on the surface of the influenza virus. This enzyme plays a critical role in the virus’s life cycle, being necessary for the release of new virus particles from infected cells.
So even if an influenza virus has successfully hijacked a cell and replicated itself many times over, by inhibiting neuraminidase, Tamiflu locks the doors, preventing the release of influenza virus from the infected cell and stopping the chain of infection.
So, blocking the viruses’ neuraminidase enzyme with Tamiflu should limit the severity of the infection and help reduce the duration of the illness.
How Tamiflu was developed
Tamiflu’s story begins in earnest in 1991 when Biota – a small Australian company – filed a patent for derivatives and analogues of a sugar molecule (a neuraminic acid) and their use as antiviral agents.
This work was carried forward by Gilead Sciences, which got to work optimising drug candidates for potent anti-neuraminidase activity and bioavailability.
Gilead initially struggled. The compounds they developed failed due to poor oral bioavailability.
In 1993, Gilead switched to using shikimic acid as a novel starting point in synthesising a new class of neuraminidase inhibitors. It was this key shift that ultimately led to the development of oseltamivir (Tamiflu), a neuraminidase inhibitor with improved oral bioavailability.
In 1996, Gilead Sciences and Roche formed a global influenza collaboration aimed at bringing Tamiflu through clinical trials and to market.
Why is shikimic acid such a good starting point for producing Tamiflu?
Shikimic acid offered Gilead an excellent starting point for the synthesis of Tamiflu because of its structure and chemical functionality, which is well-suited for creating the drug’s complex molecular structure.
- Availability: Shikimic acid is extracted from the seeds of the star anise plant, making it a readily available starting material for the industrial synthesis of antiviral drugs like Tamiflu.
- Molecular Structure: Shikimic acid is a naturally occurring compound that has a cyclohexene ring, a six-membered ring containing one double bond. This ring structure provides a good skeletal framework that closely resembles part of the Tamiflu molecule.
- Functional Groups and Stereochemistry: Shikimic acid contains several functional groups, including three hydroxyl (OH) groups, which are crucial for further chemical modifications. These groups can be chemically altered or used in reactions to attach other necessary functional groups needed in the synthesis of Tamiflu. The specific arrangement of these hydroxyl groups in shikimic acid facilitates the formation of stereochemically complex structures required for the biological activity of Tamiflu.
- Transition State Mimic: Shikimic acid provides a cyclohexene ring that helps mimic the transition state of the neuraminidase enzyme, which Tamiflu targets to inhibit. This mimicry is crucial as it allows Tamiflu to effectively bind to the neuraminidase enzyme, inhibiting its function and thus stopping the viral spread.
Approval
Tamiflu was approved by the US FDA in 1999 and by the European Medicines Agency (EMA) in 2002 for the treatment of influenza. Since then, Tamiflu has sold hundreds of millions of treatment courses worldwide, becoming one of the most widely used antiviral medications for influenza globally.
High demand
At its peak (during the bird and swine flu panics of 2005 and 2009), Tamiflu was earning Roche more than $1 billion in revenue annually. To meet such high demand, it has even been estimated that Roche was consuming 90% of the world’s star anise crop to produce Tamiflu.
Nature’s treasure chest
This blog is the first of a new series dedicated to exploring nature’s impact on the development of antiviral drugs. We’ll continue to look at how ancient traditions and folk remedies can guide drug discovery efforts and how natural product libraries can be used to screen for antivirals. So, if you are interested in how nature’s rich pharmacy has impacted (and continues to impact) modern drug development and production, you’re in the right place.
Can we help?
Do you have a promising antiviral drug candidate or library you’d like to screen? Virology Research Services can help carry your virus research project forward. Get in touch today, and one of our senior scientists will get back to you.
