People with HIV / AIDS have weakened immune systems and so are particularly susceptible to fungal infections such as cryptococcal meningitis (CM), which is caused by the fungus Cryptococcus neoformans. There are 950 000 cases of CM worldwide every year, and 625 000 deaths, making CM the leading fungal cause of death for people with HIV / AIDS. The majority of cases are in sub-Saharan Africa.
The recommended treatment for CM is a combination of flucytosine and another drug called amphotericin B, both of which feature in the World Health Organization (WHO) List of Essential Medicines. However, flucytosine is not registered for use in any African country and so cannot be prescribed as a treatment there. Flucytosine is also very expensive, as its patented manufacture involves carrying out a sequence of four chemical reactions.
That could now change thanks to the work of the CHEM21 team, who have cut the number of reactions needed from four to one. The story starts at the University of Durham in the UK, where Professor Graham Sandford and PhD student Antal Harsanyi devised a way of making flucytosine via a one-step ‘continuous flow’ method that uses the readily-available natural product cytosine as its starting point. In this technique, fluorine gas is passed through a steel tube together with a solution of cytosine in acid and, in the tube, fluorine atoms react with the cytosine molecules to make flucytosine. Because it involves just one selective reaction instead of four, the new method uses significantly less energy and raw materials and produces less waste than conventional techniques to manufacture flucytosine. It is also less expensive.
Pharmaceutical company Sanofi, which is also part of CHEM21, saw the potential of the technique and contracted MEPI, a French non-profit association, to investigate ways to scale up the process. With input from scientists from Durham and Sanofi, MEPI succeeded in setting up a small reactor capable of producing 1 kg per day of raw material. The next challenge will be for the team at Sanofi to transform the raw material into an active medicine that meets international standards. The University of Durham and Sanofi will also work on a technical and economic evaluation of the process. Meanwhile, the University of Durham has applied for a patent for the technique.
The hopes of the team are summed up in the closing paragraph of the paper published in the American Chemical Society’s Organic Process Research and Development journal: ‘This operationally simple procedure from inexpensive starting materials offers the only alternative manufacturing procedure for flucytosine to the currently operated expensive four-step process,’ they write. ‘We envisage that this one-step low cost synthesis of flucytosine will help to raise awareness of the neglected CM health epidemic and ultimately contribute to meeting the urgent requirement for large quantities of flucytosine for low income nations.’
‘This is an excellent example of how through IMI, universities and pharmaceutical companies can work together to deliver a promising discovery that addresses an unmet medical need, and then rapidly progress it to a larger scale,’ said IMI Executive Director Pierre Meulien.
The new technique could also have wider implications as flucytosine is used in the synthesis of two other important medicines: the cancer drug capecitabine and the HIV treatment emtricitabine.
CHEM21 is funded by the Innovative Medicines Initiative, a €5 billion public-private partnership between the European Union (through the European Commission’s research framework programmes) and the European pharmaceutical industry (through EFPIA, the European Federation of Pharmaceutical Industries and Associations).
Notes to Editors
Organic Process Research & Development paper: Harsanyi A, Conte A, Pichon L, Rabion A, Grenier S, Sandford G. One-step continuous flow synthesis of antifungal WHO essential medicine flucytosine using fluorine. Organic Process Research & Development, published online 5 January 2017. DOI: 10.1021/acs.oprd.6b00420
- Read the paper
- Read the American Chemical Society's news item
Catherine Brett – External Relations Manager
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About the Innovative Medicines Initiative
The Innovative Medicines Initiative (IMI) is working to improve health by speeding up the development of, and patient access to, the next generation of medicines, particularly in areas where there is an unmet medical or social need. It does this by facilitating collaboration between the key players involved in healthcare research, including universities, pharmaceutical companies, other companies active in healthcare research, small and medium-sized enterprises (SMEs), patient organisations, and medicines regulators. This approach has proven highly successful, and IMI projects are delivering exciting results that are helping to advance the development of urgently-needed new treatments in diverse areas.
IMI is a partnership between the European Union and the European pharmaceutical industry, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). Through the IMI 2 programme, IMI has a budget of €3.3 billion for the period 2014-2024. Half of this comes from the EU’s research and innovation programme, Horizon 2020. The other half comes from large companies, mostly from the pharmaceutical sector; these do not receive any EU funding, but contribute to the projects ‘in kind’, for example by donating their researchers’ time or providing access to research facilities or resources.
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CHEM21 (‘Chemical manufacturing methods for the 21st century pharmaceutical industries’) is Europe’s largest public-private partnership dedicated to the development of manufacturing sustainable pharmaceuticals. It is led by The University of Manchester and the pharmaceutical company GlaxoSmithKline and supported by the Innovative Medicines Initiative. The €26.4 million project brings together 6 pharmaceutical companies, 13 universities and 4 small to medium enterprises from across Europe. The aim is to develop sustainable biological and chemical alternatives to finite materials, such as precious metals, which are currently used as catalysts in the manufacture of medicines. Introducing biotechnology to the manufacturing processes for medicines will limit the drain on the world’s resources and have a lasting benefit on the environment. The project is establishing a European research hub to act as a source of up-to-date information on green chemistry. It is also developing training packages to ensure that the principles of sustainable manufacturing are embedded in the education of future scientists.
- More info on CHEM21: www.chem21.eu