Professor Jon R Sayers
FRSB
Clinical Medicine, School of Medicine and Population Health
Professor of Functional Genomics
+44 114 215 9552
Full contact details
Clinical Medicine, School of Medicine and Population Health
L Floor
The Medical School
Beech Hill Road
ºù«Ӱҵ
S10 2RX
- Profile
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For enquiries please contact - SMPH-West-Operational@sheffield.ac.uk
I teach graduate classes in biochemistry, protein/DNA sequence analysis, protein engineering of novel therapeutics and structure-based drug discovery.
I studied Chemistry (University of Birmingham, B.Sc. 1983) where I went on to gain a Ph.D. (1986) in the Nucleic Acids Group. Thesis title; Synthesis of Nucleoside Analogues. In 1986 I joined Fritz Eckstein’s group (Max-Planck-Institute for Experimental Medicine, Goettingen, to study restriction endonuclease-DNA interactions and helped develop a commercial system for site-directed mutagenesis (the 'phosphorothioate approach').
I also became interested in flap endonucleases, or 5'-3' exonucleases. In 1991 I moved to a Lectureship in the Biochemistry Department at the University of Wales, Bangor, UK, where I established a research group working on various aspects of molecular recognition. I moved to ºù«Ӱҵ in 1995, was promoted to Senior Lecturer in 1997, to a Readership in 1999 and a personal chair in 2006.
I have developed an interest in proteins secreted by Gram negative bacterial pathogens and how they interact with the host. We use a wide range of molecular and cell biological and biophysical techniques to unravel the detail of such interactions aided by close collaboration with structural biologists in ºù«Ӱҵ and the United States. I was elected as a Fellow of the in 2013.
In 2001 I become a director and co-founder of Asterion Ltd., a biotech spin-off company (see Asterion Ltd.) and founded DeFENition Ltd in 2016 to develop inhibitors of essential bacterial enzymes as candidate antimicrobial agents. The latter builds on over thirty years of experience in mechanistic enzymology of flap endonucleases.
I have written an article for "The Biochemist" describing the trials and tribulations of an academic involved in the setting up of a spin-out company. It can be found under the Publications, All publications tab below.
COVID-19
My laboratory responded to the Covid-19 pandemic by manufacturing large quantities of SARS-CoV-2 Nucleocapsid protein (both and ) for use in diagnostics. We have made these proteins cheaply available via the University's website.
- Research interests
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The group is involved in four main areas:
- Structure-based drug design to generate new antimicrobial agents
- Molecular mechanisms involved in protein:DNA interactions
- Microbial proteases, pathogenesis and the host response
- Biotechnology for biomedical research and drug development
Ongoing topics include the following:
A novel discovered in a 5'-3' exonuclease could explain how this class of essential replicative enzymes digest their nucleic acids substrates by a . These enzymes are involved in replication of the lagging strand during DNA synthesis and in repair of DNA damage. Some members possess structure-specific endonuclease activity as well as exonuclease and RNase H activities. We have shown that a member of this important class of enzymes contains a novel DNA-binding motif, the helical arch (see above picture of the T5 exonuclease). We are using site-directed mutagenesis, crystallography and kinetic studies to determine how these complicated enzymes function. We have cloned and expressed a number of exonucleases from bacteria including the human pathogen Haemophilus influenzae. Early mechanistic work has been funded by the BBSRC, The Wellcome Trust. Translational research in this area has been funded by Innovate UK, The Department of Health and Social Welfare and DeFENition Ltd.
Protein-DNA Recognition
Many important biological processes such as gene expression are regulated by proteins binding to specific DNA sequences. We are studying novel DNA-binding proteins from viruses and pathogenic bacteria. We have chosen proteins with no sequence homologues in the databases. Such proteins are thus unique and studying how they recognize their target sequences should provide new insights into molecular recognition processes.
We discovered a strong link between high levels of IgA1 protease production and pathogenesis in and two meningitis-causing organisms. The protease attacks IgA1, a major component of the mucosal immune system. This work has been funded by The Meningitis Research Foundation, Colin Beattie Memorial Fund and the Medical Research Council.
We are carrying out hit-to-lead programmes targeting the Flap EndoNucleases (FENs), members of the 5'-3' / 5' nuclease family which process the branched DNA structures (5′ flaps) arising during DNA replication. FENs are found as independent globular proteins in eukaryotes including parasites, and as part of DNA polymerase I in bacteria. Knockouts of genes encoding FEN enzymes have proved lethal in all organisms tested to date. We use a combination of structural studies (X ray and NMR), in silico screening and structure-based drug design to develop specific inhibitors which may one day be developed into new drugs for treating bacterial and parasite infections.
- Publications
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Show: Featured publications All publications
Featured publications
Journal articles
- . Biochemical Journal, 481(11), 669-682.
- . Scientific Reports, 6.
- . Scientific Reports, 6.
- . Nature Structural and Molecular Biology, 23, 640-646.
- . J Biol Chem, 286(35), 30878-30887.
- . Clin Sci (Lond), 119(11), 483-491.
- . Biochem J, 418(2), 285-292.
- . J Biol Chem, 282(43), 31601-31609.
- . Nat Med, 13(9), 1108-1113.
- . Nucleic Acids Res, 35(12), 4094-4102.
- Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J EXP MED, 202(10), 1319-1325.
- . Nat Struct Mol Biol, 11(5), 450-456.
- . EMBO J, 22(5), 995-1004.
- . Proc Natl Acad Sci U S A, 99(13), 8542-8547.
- . JAMA, 287(13), 1699-1705.
- . Proc Natl Acad Sci U S A, 96(1), 38-43.
- Bacteriophage collagen. SCIENCE, 279(5358), 1834-1834.
- A helical arch allowing single-stranded DNA to thread through T5 5'-exonuclease. NATURE, 382(6586), 90-93.
All publications
Journal articles
- . Biochemical Journal, 481(11), 669-682.
- . iScience, 107056-107056.
- . Wellcome Open Research, 6, 220.
- . Haematologica, 102, e336-e339.
- . Parasitology.
- . Scientific Reports, 6.
- . Scientific Reports, 6.
- . Nature Structural and Molecular Biology, 23, 640-646.
- . Growth Hormone & IGF Research, 24, S14-S15.
- . Nucleic Acids Res, 41(8), 4587-4600.
- , 227-235.
- . Nucleic Acids Research.
- . Growth Hormone & IGF Research, 22, S6-S7.
- . Growth Hormone & IGF Research, 22, S63-S63.
- . Biosci Rep, 32(6), 653-660.
- . Biochemist, 34(1), 10-15.
- . J Biol Chem, 286(35), 30878-30887.
- . PLoS ONE, 6(1).
- . Biochemistry, 49(37), 8085-8093.
- . Clin Sci (Lond), 119(11), 483-491.
- . Biochem J, 418(2), 285-292.
- . J Biol Chem, 283(42), 28741-28746.
- . Biochemist, 30(2), 8-12.
- . J Biol Chem, 282(43), 31601-31609.
- . Nat Med, 13(9), 1108-1113.
- . J Mol Biol, 371(1), 34-48.
- . Infect Immun, 75(6), 2875-2885.
- . Nucleic Acids Res, 35(12), 4094-4102.
- Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J EXP MED, 202(10), 1319-1325.
- . Biochem Soc Trans, 32(Pt 6), 1130-1132.
- Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand 1 on macrophages. J IMMUNOL, 173(2), 1240-1248.
- . Nat Struct Mol Biol, 11(5), 450-456.
- . EMBO J, 22(5), 995-1004.
- . J Mol Biol, 320(5), 1025-1035.
- . Proc Natl Acad Sci U S A, 99(13), 8542-8547.
- . JAMA, 287(13), 1699-1705.
- . Trends Biotechnol, 19(11), 429-430.
- . Biochemical Journal, 357(3), 779-785.
- . Biochem J, 357(Pt 3), 779-785.
- . Nucleic Acids Res, 29(13), 2772-2779.
- . Trends Biochem Sci, 26(3), 149-150.
- . Biochemical Society Transactions, 29(1), A30-A30.
- . Biochemical Society Transactions, 29(1), A30-A30.
- . Biochemical Society Transactions, 29(1), A30-A30.
- . Anal Biochem, 288(2), 230-232.
- . J Biol Chem, 274(25), 17711-17717.
- . Biochemical Society Transactions, 27(3), A127-A127.
- . Nucleic Acids Res, 27(3), 730-735.
- . FASEB J, 13(2), 331-337.
- . Proc Natl Acad Sci U S A, 96(1), 38-43.
- Structure-specific DNA cleavage by 5 ' nucleases. TRENDS BIOCHEM SCI, 23(9), 331-336.
- . Nat Struct Biol, 5(8), 668-670.
- Bacteriophage collagen [5] (multiple letters). Science, 279(5358), 1834.
- Bacteriophage collagen. SCIENCE, 279(5358), 1834-1834.
- . Nucleic Acids Res, 25(21), 4224-4229.
- . Nucleic Acids Res, 25(19), 3801-3807.
- . Parasitology, 115 ( Pt 3), 237-247.
- Cloning, heterologous expression and antigenicity of a schistosome cercarial protease. PARASITOLOGY, 114, 447-453.
- . Anal Biochem, 241(2), 186-189.
- A helical arch allowing single-stranded DNA to thread through T5 5'-exonuclease. NATURE, 382(6586), 90-93.
- . PARASITOLOGY TODAY, 12(3), 124-125.
- . Methods Enzymol, 275, 227-238.
- AGA/AGG CODON USAGE IN PARASITES - IMPLICATIONS FOR GENE-EXPRESSION IN ESCHERICHIA-COLI. PARASITOL TODAY, 11(9), 345-346.
- . Biodegradation, 5(3-4), 195-217.
- . J Theor Biol, 170(4), 415-421.
- . Microbiology, 140 ( Pt 9), 2305-2307.
- . J Mol Biol, 233(1), 179-182.
- SITE-DIRECTED MUTAGENESIS OF SINGLE-STRANDED AND DOUBLE-STRANDED DNA BY PHOSPHOROTHIOATE APPROACH. METHODS IN ENZYMOLOGY, 217, 189-217.
- . NUCLEIC ACIDS RESEARCH, 20(20), 5476-5476.
- RAPID HIGH-EFFICIENCY SITE-DIRECTED MUTAGENESIS BY THE PHOSPHOROTHIOATE APPROACH. BIOTECHNIQUES, 13(4), 592-596.
- . Expert Opinion on Therapeutic Patents, 2(7), 1023-1029.
- . NUCLEIC ACIDS RESEARCH, 19(15), 4127-4132.
- Properties of overexpressed phage T5 D15 exonuclease. Similarities with Escherichia coli DNA polymerase I 5'-3' exonuclease.. J Biol Chem, 265(30), 18311-18317.
- Inhibition of the restriction endonuclease BanII using modified DNA substrates. Determination of phosphate residues critical for the formation of an active enzyme-DNA complex.. J Biol Chem, 265(24), 14389-14394.
- . Nucleic Acids Res, 17(22), 9495.
- . Nucleosides and Nucleotides, 7(5-6), 625-628.
- . Nucleic Acids Res, 16(3), 791-802.
- . Nucleic Acids Res, 16(3), 803-814.
- . J Med Chem, 31(1), 268-271.
- . Tetrahedron, 43(20), 4601-4608.
- . Nature Communications, 15(1).
- . Antimicrobial Agents and Chemotherapy.
- . Wellcome Open Research, 6, 220-220.
- . Wellcome Open Research, 6, 220-220.
- . Endocrine Abstracts.
- . Endocrine Abstracts, 1-1.
- . Biochemical Journal, c1-c1.
Chapters
- Bacteriophage T5 In Calendar R (Ed.), The Bacteriophages (pp. 268-276). Oxford University Press
- Phosphorothioate-based site-directed mutageneis In Creighton TE (Ed.), Protein function (pp. 279-295). Oxford University Press, USA
- Phosphorothioate-based site directed mutagenesis In McPherson MJ (Ed.), Directed mutagenesis (pp. 49-59). Oxford University Press, USA
- Phosphorothioate-based oligonucleotide-directed mutagenesis In Setlow JK (Ed.), Genetic Engineering (pp. 109-122). Plenum Pub Corp
Conference proceedings papers
- Immunogenicity, Toxicology, Pharmacokinetics and Pharmacodynamics of Growth Hormone Ligand-Receptor Fusions.. ENDOCRINE REVIEWS, Vol. 31(3)
- Comh: Isolation, purification and characterisation of a unique H-pylori protein. GASTROENTEROLOGY, Vol. 132(4) (pp A212-A213)
- ComH: Isolation, purification and characterisation of a unique H pylori protein. GUT, Vol. 56 (pp A55-A55)
- ComH: Purification of a unique H pylori protein. GUT, Vol. 54 (pp A86-A86)
- Isolation of a novel TNF regulating protein.. ARTHRITIS AND RHEUMATISM, Vol. 42(9) (pp S201-S201)
- Mechanistic studies of a 5 ' nuclease from T5 bacteriophage. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 2 (pp 161-167)
- PHOSPHOROTHIOATE BASED MUTAGENESIS OF SINGLE AND DOUBLE-STRANDED DNA VECTORS. SITE-DIRECTED MUTAGENESIS AND PROTEIN ENGINEERING (pp 171-179)
- . NUCLEOSIDES & NUCLEOTIDES, Vol. 10(1-3) (pp 665-667)
- PHOSPHOROTHIOATE-DNA FOR OLIGONUCLEOTIDE-DIRECTED MUTAGENESIS. BIOLOGICAL CHEMISTRY HOPPE-SEYLER, Vol. 368(9) (pp 1036-1036)
Patents
- Modified growth hormone fusion polypeptides. US7524649 B2 (USA). Appl. 28 Apr 2009.
- MODIFIED GROWTH HORMONE POLYPEPTIDES. WO/2009/047474 Appl. 16 Apr 2009.
- GROWTH HORMONE FUSION PROTEINS. WO/2009/013461 Appl. 29 Jan 2009.
- . Appl. 01 Dec 2006.
- Designer proteases. US6,383,775 (USA). Appl. 01 Jan 1970.
- Growth hormone fusion proteins. 8,470,559 (USA). Appl. 01 Jan 1970.
- Fusion protein comprising growth hormone and growth hormone receptor. 7,446,183 Appl. 01 Jan 1970.
- Cytokine polypeptides and antibodies containing a signal sequence for the attachment of glycosylphosphatidylinositol. US 7,625,998 (USA). Appl. 01 Jan 1970.
Preprints
- Teaching interests
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I teach graduate-level biochemistry, molecular & structural biology, bioinformatics and biotechnology in relation to biomedical research and drug discovery.
- Professional activities and memberships
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- Director, , 2001 - 2009.
- Trustee, Biochemical Society Pension Scheme, 2008 - 2017
- Honorary Treasurer and Trustee of the , 2008-2012.
- Director of Portland Press, 2008-2012.
- Editorial board member of , 2007 - 2015.
- Founding Director, DeFENition Ltd.
Granted patents:
- Ross R, Artymiuk P, Sayers J. Growth hormone fusion proteins. 2013, Granted US Patent No. 8,470,559.
(PLEASE NOTE although this has the same title and author as patent no. 8,293,709 which was already included, it is a separate patent granted in 2013). - Ross R, Artymiuk P, Sayers J. Growth hormone fusion proteins. 2012, Granted US Patent No. 8,293,709.
- Artymiuk, P, Ross R, Sayers J. Modified growth hormone polypeptides 2012, Granted US Patent No. 8,273,552.
- Ross R, Artymiuk P, Sayers J. Fusion protein comprising growth hormone and growth hormone receptor. 2012 Granted US Patent No. 8,173,782.
- Ross R, Sayers J, Artymiuk P. Modified growth hormone fusion polypeptides, 2009, Granted US Patent No. 7524649.
- Ross R, Sayers J, Artymiuk P. Cytokine polypeptides and antibodies containing a signal sequence for the attachment of glycosylphosphatidylinositol, 2009, Granted US Patent No. 7625998.
- Ross R, Artymiuk P, Sayers J. Fusion protein comprising growth hormone and growth hormone receptor. 2008 Granted US Patent No. 7,446,183.
- Duff, G.W., Sayers, J.R., Vitovski, S. Designer proteases. 2002 Granted US Patent No.6,383,775.