Research

Chemical Genetics

In vivo control of protein function using small molecules

The field of Chemical Genetics is based on the premise that small molecules may be used to perturb the cellular functions of specific proteins.  Small molecules are titrated into cells, thereby perturbing the function of a particular macromolecule.  The approach may be used to understand the role of target protein in its cellular context.

Chemical Genetics is a major area of expansion at the University of Leeds, which has been supported by £2M investment.  The initiative is highly interdisciplinary, and involves de novo ligand design, chemical synthesis (especially diversity oriented synthesis), bioanalytical chemistry and cell biology.  Current projects in this area are focussed on the elucidation of a range of biological mechanisms in different areas of cell biology: from the mechanism which control stem cell fate, to those which control transcription and the transport of molecules into cells.

Publications in this area:

145 Gail  Bartlett , Som  Dutt, Thomas  Edwards , Zsofia  Hegedus, Frizsina  Hobor, Katherine  Horner , Amaurys  Ibarra, Adam  Nelson , Kristina  Parashiv , Richard  Sessions , Kirstin  Spence, Andrew  Wilson and Dek  Woolfson , "Predicting and Experimentally Validating Hot-Spot Residues at Protein-Protein Interfaces", ACS Chem. Biol. 2019, , DOI: 10.1021/acschembio.9b00560
Keywords: "Chemical Genetics"

142 Chris  Arter , Richard  Bayliss , Patrick  Collins, Daniel  Foley , Patrick  McIntyre, Frank  von Delft and Stuart  Warriner , "Construction of a Shape‐Diverse Fragment Set: Design, Synthesis and Screen against Aurora‐A Kinase", Chem. Eur. J. 2019, 25, 6831-6839
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

141 Shiao  Chow , Joan  Mayol Llinas and Adam  Nelson , "Expansion of the structure-activity relationships of BACE1 inhibitors by harnessing diverse building blocks prepared using a unified synthetic approach", MedChemComm 2019, 10, 616-620
Keywords: "Chemical Genetics"

139 Adam  Nelson and Nicholas  Westwood, "Synthetic Tools for Elucidating Biological Mechanisms", Chemical and Biological Synthesis: Enabling Approaches for Understanding Biology 2018, , 1-7
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

138 Adam  Nelson and Nicholas  Westwood, "Chemical and Biological Synthesis: Enabling Approaches for Understanding Biology", Royal Society of Chemistry 2018, ,  ISBN: 978-1-78262-948-1
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

137 Anthony  Aimon , Mark  Dow , Tuomo  Kalliokoski, George  Karageorgis , Steve  Marsden , Remy  Morgantin , Adam  Nelson and Didier  Roche, "Translation of innovative chemistry into screening libraries: an exemplar partnership from the European Lead Factory", Drug Discovery Today 2018, 23, 1578-1583
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

130 George   Burslem , Thomas  Edwards , Hannah  Kyle , Adam  Nelson and Andrew  Wilson , "Hypoxia inducible factor (HIF) as a model for studying inhibition of protein-protein interactions", Chem. Sci. 2017, 8, 4188-4202
Keywords: "Chemical Genetics"

129 Katherine  Abrahams, Del  Besra, Mark  Dow , Adam  Nelson , Luis  Vaz and Stuart  Warriner , "Modular Synthesis of Diverse Natural Product-like Macrocycles: Discovery of Hits with Antimycobacterial Activity", Chem. Eur. J. 2017, 23, 7207-7211
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

1 Anthony  Aimon , Patrick  Collins, Philip  Craven , Richard  Doveston , Daniel  Foley , Steve  Marsden , Adam  Nelson , Romain  Talon and Frank  von Delft, "Synthesis and Demonstration of the Biological Relevance of sp3-rich Scaffolds Distantly Related to Natural Product Frameworks", Chemistry - A European Journal 2017, 23, 15227–15232
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

120 Alex   Breeze , George   Burslem , Thomas  Edwards , Hannah  Kyle , Adam  Nelson , P  Prabhakaran, Stuart  Warriner and Andrew  Wilson , "Synthesis of highly functionalised oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups", Org. Biomol. Chem. 2016, 14, 3782-3786
Keywords: "Chemical Genetics"

119 Alex   Breeze , George   Burslem , Thomas  Edwards , Hannah  Kyle , Adam  Nelson , Stuart  Warriner and Andrew  Wilson , "Towards ‘bionic’ proteins: replacement of continuous sequences from HIF-1alpha with proteomimetics to create functional p300 binding HIF-1alpha mimics", Chem. Commun. 2016, 52, 5421-5424
Keywords: "Chemical Genetics"

113 Alex   Breeze , George   Burslem , Thomas  Edwards , Hannah  Kyle , Adam  Nelson , Jonathan  Stott, Darren  Tomlinson , Stuart  Warriner , Kate  Wickson and Andrew  Wilson , "Exploration of the HIF-1alpha/p300 binding interface using peptide and adhiron phage display technologies to locate binding hot-spots for inhibitor development", Mol. Biosys. 2015, 11, 2738-2749
Keywords: "Chemical Genetics"

105 Alex   Breeze , George   Burslem , Thomas  Edwards , Hannah  Kyle , Adam  Nelson , Stuart  Warriner and Andrew  Wilson , "Small Molecule Proteomimetic Inhibitors of the HIF-1alpha/p300 Protein-Protein Interaction", ChemBioChem 2014, 14, 1083-1087
Keywords: "Chemical Genetics"

102 Sandra  Bell, Jackie  Bond, Julie  Higgins, Heather  Martin , Ewan  Morrison, Adam  Nelson , Darren  Tomlinson and Stuart  Warriner , "High-Content, High-Throughput Screening for the Identification of Cytotoxic Compounds Based on Cell Morphology and Cell Proliferation Markers", Plos ONE 2014, 9, e88338
Keywords: "Chemical Genetics"

99 Ramkrishna  Basak , Martin  Fisher , Colin  Fishwick , Arnout  Kalverda , Adam  Nelson and Bruce  Turnbull, "Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility", Org. Biomol. Chem. 2014, 12, 486-494
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

90 Catherine  Joce , Adam  Nelson , Peter  Stockley, Stuart  Warriner and Rebecca  White, "Design, Synthesis and In Vitro Evaluation of Novel Bivalent S-Adenosylmethionine Analogues", Bioorg. Med. Chem. Lett. 2012, 22, 278-284
Keywords: "Chemical Genetics"

89 Mark  Dow , Martin  Fisher , Tom   James , Francesco  Marchetti and Adam  Nelson , "Towards the systematic exploration of chemical space", Org. Biol. Chem. 2012, , in press
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

87 Heather  Bone , Adam  Nelson and Melanie  Welham, "A novel chemically directed route for the generation of definitive endoderm from human embryonic stems cells based on inhibition of GSK-3", J. Cell Sci. 2011, 124, 1992-2000
Keywords: "Chemical Genetics"

85 Martin  Fisher and Adam  Nelson , "The Chemical Genetic Approach: The Interrogation of Biological Mechanisms with Small Molecule Probes", New Frontiers in Chemical Biology: Enabling Drug Discovery, ed. M. E. Bunnage 2011,
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

75 Jamie  Caryl , Catherine  Joce , Adam  Nelson , Peter  Stockley and Stuart  Warriner , "Identification of stable S-adenosylmethionine (SAM) analogues derivatised with bioorthogonal tags: Effect of ligands on the affinity of the E. coli methionine repressor, MetJ, for its operator DNA", Org. Biomol. Chem. 2009, 7, 635-638
Keywords: "Chemical Genetics"

74 Chris  Cordier , Stuart  Leach , Daniel  Morton , Adam  Nelson and Stuart  Warriner , "Synthesis of natural product-like molecules with over eighty distinct skeletons", Angew. Chemie. Int. Ed. 2009, 48, 104-109
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

73 Steve  Bartlett , Heather  Bone , Teresa  Damiano , Julie  Letchford , Adam  Nelson , Alexis  Perry and Melanie  Welham, "Involvement of glycogen synthase kinase-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides", Chem. Biol. 2008, 16, 15-27
Keywords: "Chemical Genetics"

70 Chris  Cordier , Daniel  Morton , Sarah  Murrison , Adam  Nelson and Catherine  O'Leary-Steele , "Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries", Nat. Prod. Rep. 2008, , 719-737
Keywords: "Chemical Genetics" "Diversity-oriented synthesis"

63 Chris  Adams, Alison  Ashcroft, Andy  Baron, Blandine  Clique , Alan  Ironmonger , Adam  Nelson , Peter  Stockley and Ben  Whittaker , "Scanning conformational space with a library of stereo- and regiochemically diverse aminoglycoside derivatives: The discovery of new ligands for RNA hairpin sequences", Org. Biomol. Chem. 2007, 5, 1081-1086
Open Access Version
Keywords: "Stereochemically diverse libraries" "Chemical Genetics"

62 Craig  Beck, Heather  Bone , Pierre-Yves   Bourillot, Teresa  Damiano , Adam  Nelson , Pierre  Savatier, Valerie  Schreiber, Mike   Storm and Melanie  Welham, "Regulation of Nanog expression by phosphoinositide 3-kinase-dependent signalling in murine embryonic stem cells ", J. Biol. Chem. 2007, 282, 6265-6273
Open Access Version - provided courtesy of, and copyright held by, the American Society of Biochemistry and Molecular Biology
Keywords: "Chemical Genetics"

58 Adam  Nelson , "Building bridges between Chemistry and Biology", RSC Chemical Biology Forum Newsletter Autumn 2005, , 3-4
Keywords: "Chemical Genetics"

56 Chris  Cordier and Adam  Nelson , "Reaching the target: small molecules aim to probe barrier quality", ChemBioChem , 6, 1953-1955
Open Access Version - provided courtesy of John Wiley and Sons
Keywords: "Chemical Genetics"

55 Alex  Bullock, J. E.  Debreczeni, O. Y.  Fedorov, Stefan  Knapp, Brian  Marsden and Adam  Nelson , "Structural Basis of Inhibitor Specificity of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM-1) Kinase", J. Med. Chem. 2005, 48, 7604-7614
Keywords: "Stereochemically diverse libraries" "Chemical Genetics"

52 Steve  Bartlett , Godfrey  Beddard, Richard  Jackson, Veysel  Kayser, Colin  Kilner , Andrew  Leach, Adam  Nelson , Peter  Oledzki, Peter  Parker, Gavin  Reid and Stuart  Warriner , "Comparison of the ATP binding sites of Protein Kinases using conformationally diverse bisindolylmaleimides", J. Am. Chem. Soc. 2005, 127, 11699-11708
Keywords: "Stereochemically diverse libraries" "Chemical Genetics"

50 Blandine  Clique , Jackie  Colley , Alan  Ironmonger , Adam  Nelson , Peter  Stockley, James  Titchmarsh and Ben  Whittaker , "Synthesis of a library of stereo- and regiochemically diverse aminoglycoside derivatives", Org. Biomol. Chem. 2005, 3, 2776-2785
Open Access Version - provided courtesy of the RSC
Keywords: "Stereochemically diverse libraries" "Chemical Genetics"

39 Steve  Bartlett and Adam  Nelson , "Towards configurationally stable bisindolylmaleimide cyclophanes: Potential tools for investigating protein kinase function", Chem. Commun. 2004, , 1112-1113
Open Access Version - provided courtesy of the RSC
Keywords: "Stereochemically diverse libraries" "Chemical Genetics"

People currently working in this research area:

Gail Bartlett

Richard Bayliss

Sergio Celis

Thomas Edwards

Zsofia Hegedus

Steve Marsden

Adam Nelson

Richard Sessions

Aisha Syed

Stuart Warriner

Nicholas Westwood

Jack White

Andrew Wilson