Exploitation of Biomolecules & Bioconjugates in Medicine & Biotechnology

These probes have revealed mechanism and become tools that enable diagnosis, monitoring and treatment of disease.

By exploiting a mechanistic understanding of such ligand-protein interactions, direct interrogation (in vivo imaging) of molecular interactions in organisms has been accomplished by us using reporter groups that are detectable by non-invasive (NMR, MRI, optical, fluorescent & radioemission) imaging methods. In 2007, we demonstrated the first examples of synthetic analogues of human proteins to show good functional mimicry in vivo.[pub 85] Unlike antibodies, these probes were effective in revealing pathogenesis associated with disease (MS, cerebral malaria) through direct mimicry of biotic processes, thus uniquely revealing disease mechanism. The development of probes & imaging methods along these lines is in its infancy but has now been rapidly adopted by several groups. Our functional & molecular imaging probes have been developed for disease detection and image-guided therapy using PET, gamma scintigraphy[pub 55][pub 137], MRI[pub 106] & fluorescence[pub 155][pub 197]. The first in vivo uses of glyco-nanoparticles (& variants) in 2009 allowed MRI biomarker detection for multiple sclerosis & stroke diagnosis[pub 106]. The first selective, small-molecule probe of TB[pub 155] is now being tested in clinics and is available commercially. This use of precise molecular information in imaging is now referred to, by some, as ‘Molecular Imaging’.

In addition to allowing imaging, such probes and bioconjugates can act therapeutically (either directly or by carrying a cargo). Prodrug,[pub 55] gene,[pub 60] polymer,[pub 70] and radiation[pub 137] delivery systems have all been developed by the group. The first carbohydrate-targeted enzyme drug-delivery systems, discovered in 2004, were applied to tumour treatment[pub 55] and developed with GlaxoSmithKline, licensed by Biotech and pre-clinically evaluated. The first glycopolymer prodrug allowed antioxidant delivery to prolong cell lifespans (with Cameron).[pub 70] The first in vivo uses of filled-functionalized carbon-nanotubes in 2010 allowed targeted delivery of the highest known radiation doses into organisms (with Green)[pub 137] and has spawned an EU research network (RADDEL) for its clinical exploitation.

We have also created therapeutic systems based on synthetic proteins that have direct function. Enzymes bearing targeting-ligands can selectively destroy disease-associated proteins with complementary binding sites.[pub 51] Synthetic mimics of protein therapeutics such as EPO were developed through the Biotech ‘spin-out’ Glycoform (with Fairbanks).[pub 48] The first successful, non-self glycoconjugate vaccines used modified glycans to induce enhanced antibody titres;[pub 144] this licensed method has now been applied to HIV1 & meningitis vaccine candidates. Chemically-induced and reprogrammed adenovirus tropism[pub 60] is a general strategy, with IP assigned to industry, and has now been applied to successful 'DNA vaccination' strategies. Synthetic virus-mimics with extreme valencies (>1000) of glycan act as decoys to potently block viral infection.[pub 179] Chemically-phosphorylated synthetic antibodies built by our group show enhanced selectivity as a result of ‘triggering’ by disease-associated signaling cascades.[pub 197]

We believe that such synthetic biomolecule diagnostics and therapeutics ('synthetic biologics') have the potential, developed through this form of ‘Synthetic Biology’, to parallel the emergence in the 20th century of unnatural small-molecule therapeutics (‘drugs’), as developed by Synthetic Organic Chemistry.

Prof Benjamin G. Davis
University of Oxford
Chemistry Research Laboratory
Mansfield Road
Oxford, OX1 3TA, UK
Phone: + 44 (0)1865 275652
Fax: + 44 (0)1865 275674