Creating new anti-viral and cancer drugs
ProTide technology is a pro-drug strategy with proven capacity to generate new drug candidates for nucleoside-based antiviral and anti-cancer indications.
Finding new drugs to treat some of the world's most common forms of virus and cancers is a key challenge for scientists and pharmaceutical companies worldwide. The challenge remains to develop antivirals for the treatment of HIV, hepatitis B (HBV) and HCV.
The McGuigan-led research showed the chemically-protected phosphate prodrugs to be stable to common extracellular deactivating enzymes that typically cause poor pharmacokinetics. Importantly the lipophilic character of the ProTide motif enables intracellular prodrug delivery by passive membrane permeation rather than relying on active transport.
This is a highly desirable pharmaceutical feature for delivery of drugs to intracellular targets and for oral drug administration. Crucially the team showed it could manipulate the design of the ProTide to maximise the efficacy of a drug while minimising its potential systemic toxicities.
Out-licencing of the intellectual property for the technology has enable reinvestment in facilities within the School of Pharmacy to expand the programme of research.
McGuigan's team has been at the forefront of candidate ProTide drug development particularly in anti-virals, including the design of a hepatitis C (HCV) drug candidate. The ProTide technology has also been applied to modify and improve nucleoside-based anticancer agents.
- McGuigan, C. et al. 2011. Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside. Journal of Medicinal Chemistry 54 (20), pp.7247-7258. (10.1021/jm200815w)
- McGuigan, C. et al. 2010. Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. Biorganic and Medicinal Chemistry Letters 20 (16), pp.4850-4854. (10.1016/j.bmcl.2010.06.094)
- Balzarini, J. et al., 1996. Mechanism of anti-HIV action of masked alaninyl d4T-MP derivatives. Proceedings of the National Academy of Sciences 93 (14), pp.7295-7299.
- McGuigan, C. et al. 1996. Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. Journal of Medicinal Chemistry 39 (8), pp.1748-1753. (10.1021/jm950605j)