Research

The Serpell Group works on the supramolecular chemistry of macromolecules. Our aim is to exploit the breadth and depth of supramolecular chemistry, chemical biology, and nanotechnology, forging new links and generating new chemical structures, functions, and technologies.

We also contribute wherever we can to diverse projects led by other scientists.

Phosphoestamers: sequence-defined polyphosphoesters

Sequence-definition is the key property of proteins and nucleic acids which gives them their outstanding functions in biology. We are interested in harnessing sequence-definition in the synthetic world to address therapeutic needs. In our lab, we have adapted the automated phosphoramidite method used to produce convention nucleic acids to yield sequence-defined poly/oligophosphoesters (phosphoestamers) which, like proteins and nucleic acids, display folding and self-assembly according to their monomer sequence.

We are using phosphoestamers in fundamental science – learning to understand sequence/3D structure relationships in a new context – and also for serious medical needs such as inhibition of challenging protein-protein interactions and responsive drug delivery.

Sequence-defined phosphoestamers for selective inhibition of the KRASG12D/RAF1 interaction, Chem. Sci., 2025, 16, 113-123

Sequence-complementarity dependent co-assembly of phosphodiester-linked aromatic donor-acceptor trimers, Chem. Commun., 2022, 58, 12200-12203

Sequence Isomerism in Uniform Polyphosphoesters Programmes Self-Assembly and Folding, Chem. Commun., 2020, 56, 5307-5310

Chemically modified nucleic acids

The chemical synthesis of oligonucleotides opens up many possibilities for fine-tuning their behaviour and interactions in biology. We are particularly interested in controlling their supramolecular chemistry: host-guest chemistry and self-assembly.

Aptamers show excellent molecular recognition properties, and could be more sustainable and versatile replacements for antibodies, however they lag behind in biological applications because of their lower affinity, selectivity, and biostability. We are advancing aptamers by identifying non-natural modifications (any type, in any position on the sequence) which improve these aspects through a non-enzymatic selection process.

Nucleic acid self-assembly is dominated by base pairing, which has opened up vast possibilities in DNA nanotechnology. However, when other self-assembly systems are combined with DNA nanotechnology, more intricate, or unpredictable properties can emerge. We are introducing new aspects to DNA assembly through the integration of peptides and polymers to create new functional, dynamic, and biologically relevant nanostructures.

Selection of Optimised Ligands by Fluorescence-Activated Bead Sorting, Chem. Sci., 2023, 14, 9517-9525

Tuning dynamic DNA- and peptide-driven self-assembly in DNA-peptide conjugates, Chem. Sci., 2023, 14, 196-202

Precision Polymers and 3D DNA Nanostructures: Emergent Assemblies from New Parameter Space, J. Am. Chem. Soc., 2014, 136, 15767-15774

Chemical biology of natural products for global healthcare

The world is still full of medical problems waiting to be solved. There is also great biodiversity, which leads to a huge range of natural products which may have some of the desired medical activity. There are many reports of such findings, however many of these studies do not progress beyond initial discovery, and there are important questions to be answered about mechanism, pharmacokinetics, and structure-activity relationships which need to be answered before a new drug can reach the market. We are interested in making these discoveries, working particularly with partners in lower and middle income countries to develop home-grown solutions to global healthcare needs.

We are work with partners in Viet Nam to uncover the mechanism of action of madecassic acid, a compound found in a local crop which has promising activity against liver cancer which is a huge problem there. Our scope reaches beyond medicinal chemistry, and use of the tools of chemical biology, into sustainable agriculture and social science of modern/traditional crossover medicines. We are also working with partners in Malaysia on compounds which could target colorectal cancer and obesity.

Synthesis and cytotoxic activity of madecassic acid–silybin conjugate compounds in liver cancer cells, RSC Med. Chem., 2024,15, 3418-3432

Comparison of organic and conventional production methods in accumulation of biomass and bioactive compounds in Centella asiatica (L.) urban, ChemRxiv, 2013, DOI: 10.26434/chemrxiv-2023-q9vvc

Hydroxylated polymethoxyflavones reduce the activity of pancreatic lipase, inhibit adipogenesis and enhance lipolysis in 3T3-L1 mouse embryonic fibroblast cells, Chem. Biol. Interact., 2023, 379, 110503