Chemistry at the University of Liverpool

Medicinal and Bio-nano Chemistry

Research

The Liverpool Medicinal and Bio-nano Chemistry cluster has made a range of important contributions during the assessment period including understanding the mechanisms of drug-action of the 4-aminoquinolines, quinolone antimalarials (PNAS 2015) and peroxide-based antimalarials (ACIE 2016, PNAS 2016, Nature Comm 2017), conducting the world’s first human trial of an orally-dosed HIV nanomedicine, and the first demonstration of long-term malaria prevention from injected antimalarial nanoparticles (Nature Comm. 2018)

Electrostatic potential of active anti-tuberculosis compound

Research projects across the cluster operate at all levels of the drug discovery pipeline, including clinical trials in humans (Isoquine, Phase 1 with GSK/ Medicines for Malaria Venture (MMV) 2008; HIV nanomedicines with the Clinton Health Access Initiative (CHAI) and St Stephen’s AIDS - ACIE 2010, PNAS 2012, JMC 2009, Nature Comm 2016).

In total, three of our projects have contributed to the portfolio of the MMV, the largest portfolio of antimalarial drugs developed, and Liverpool is the first academic collaboration partner of the UNITAID-funded Medicines Patent Pool for novel HIV therapies. More recently, cluster members have candidate selected a new molecule, AWZ1066, a first in class synthetic azaquinazoline treatment for the filarial diseases lymphatic filariasis and onchocerciasis (PNAS 2019). With Astra Zeneca and LSTM, we have also completed the largest neglected tropical diseases screening campaign in history (AWOL, filariasis) with cheminformatic hit selection and triaging from over 1.4 million compounds (Nature Comm. 2019). Strong interactions with large and small companies, hospitals and charities including Pfizer, AstraZeneca, Gilead, Cipla, Abbott and Merck, Médecins Sans Frontières, Clinton Health Access Initiative, St Stephen’s AIDS Trust, British Society for Antimicrobial Chemotherapy, Fight for Sight, Liverpool Health Partners and the Drugs for Neglected Diseases Initiative has led to considerable support for research across the cluster with government funding coming from EPSRC, MRC, Bill and Melinda Gates Foundation, MRC and NIH(US).

Potent novel insecticide docked into the binding site of the Na channel

In terms of novel synthetic methodology the cluster has published important new synthetic methodologies with broad synthetic applications such as cross-coupling chemistry of sulfoxonium ylides with C-H bonds, rhodium catalysed carbocyclisation chemistry by activation of olefinic C-H bonds. (ACIE 2014, ACIE 2017) and an unprecedented selective cleavage of arene rings by direct insertion of iridium into aromatic rings (ACIE 2017).

In mechanistic work published in Science 2017, macrocyclic rings have been prepared photochemically to study the influence of strain on the rates of reactions that cleaved either phosphorus-oxygen or silicon-oxygen bonds.

In terms of green chemistry and industrial biotechnology (AJC), new enzymes are being discovered and developed for conversion of biomass derived materials into biodegradable bioplastics (Green Chem. 2015). A one-pot multienzyme bioconversion was demonstrated (Green Chem. 2017) for the highly efficient conversion of cellulose-derived feedstock HMF into bioplastics precursor FDCA and this is being scaled up for commercialisation with Biome Bioplastics with Innovate UK support. With funding from BBSRC, EPSRC and IUK, new enzymes are being developed for conversion of FDCA and related lignin-derived dicarboxylic acids into bioplastics and also for recycling of waste plastic (Nature Comm. 2019).

Work has also been conducted on the chemistry of the 8-nitroguanine DNA lesion which is increasingly associated with inflammation-related carcinogenesis. In particular, a very sensitive method for detecting this lesion in DNA has been developed (Chem. Eur. J. 2017) and a potential enzymatic repair mechanism that involves a reductive denitration has been proposed (Chem. Eur. J. 2018).

Collectively, the cluster has published 30 patent family applications during the assessment period, both UoL and collaborative filings with industry.