Rational Design, Synthesis and Biological Evaluation of Benzimidazoles; Towards a Novel Therapy Selectively Targeting C. neoformans beta-tubulin

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The Need:Cryptococcus neoformans (C. neoformans) is a yeast like fungus which manifests as meningitis and less frequently pneumonia within the human body. In sub-Saharan Africa C. neoformans causes more deaths annually than tuberculosis. C. neoformans is the most common cause of fungal infection in patients with AIDS and there are an estimated 1 million cases of cryptococcal meningitis worldwide each year. The current drugs used to treat this disease are a 2 week course of amphotericin B and 5-flucytosine followed by a long term course of fluconazole. Amphotericin B and 5-flucytosine are associated with toxicity and fluconazole suppresses the growth of the fungus but does not completely remove it from the body. There is a therefore a great need for new drugs to treat C. neoformans infections. These drugs must have less toxicity and work better against the disease. The aim of this proposal is to complete the early stage drug discovery activities required to ultimately develop new drugs for cryptococcal meningoencephalitis that can be used in sub-Saharan Africa.The Concept:It has previously been reported within scientific papers that a class of compound called the benzimidazoles (widely used to treat worm infections in humans and as fungicides in agriculture) have good activity against C. neoformans in a laboratory and this has subsequently been confirmed by work here at the University of Liverpool (UoL). Benzimidazoles have been shown to interfere with cell division in C. neoformans through binding to beta-tubulin. Beta-tubulin is a protein that is essential for cell division and growth, when benzimidazoles bind to beta-tubulin the fungal cell can no longer grow. More recently, unpublished studies carried out at UoL have shown flubendazole to be active against C. neoformans in the mouse model. Humans also have beta-tubulin so it is essential that any new drug developed against the beta-tubulin target is selective for C. neoformans beta-tubulin. Medicinal chemistry (modification of the chemical structure of a drug) can be used to improve both selectivity for beta-tubulin and activity against C. neoformans.The Solution:Identification of an active class of compound, against a known target, with established whole cell C. neoformans and animal model activity provides an excellent starting point for medicinal chemistry modification. To date benzimidazole compounds have never undergone medicinal chemistry optimisation to establish beta-tubulin selectivity or to improve C. neoformans activity. The two most commonly use benzimidazole drugs (Flubendazole and albendazole) are extensively metabolised within the body and have a limited ability to move from the stomach into the blood stream. New compounds will be designed using information from computer models to predict how they are likely to behave within the body. In order to improve the safety profile of the newly designed compounds their selectivity for C. neoformans beta-tubulin over human beta-tubulin will be measured in the laboratory (alongside activity against C. neoformans) and computer models of the binding sites of the two tubulins used to look at how new compounds are likely to bind better with C. neoformans beta-tubulin. Once C. neoformans activity, selectivity for beta-tubulin and improved levels of circulating drug have been established the compounds will move into a mouse model of C. neoformans infection. Impact:The long term aim is to develop a single therapy that does not require subsequent long term treatment with fluconazole and that can be given both orally and by injection. Given the number of patients affected by C. neoformans this project has the potential to have a dramatic beneficial impact on individuals and societies.Development:Compounds demonstrating activity in the mouse model will form the basis of further funding applications to progress the new drugs through the drug development pipeline.