The Protein and Peptide Science Group

Committee Members:

Chairman: Brian Austen, St George's Hospital Medical School, Cranmer Terrace, LONDON SW17 ORE

Tel: 01817255651. Fax: 01817253594

Email [email protected]

Secretary: John Deadman, Thrombosis Research Institute. Sir Emmanuel Kaye Building, Manresa rd, LONDON SW3 6LR

tel: 020 7351 8319, fax: 020 7351 8324

Email: [email protected]

Treasurer: Parvez Haris, De Montfort University, Leicester

Email: [email protected]

Committee:

Mark Dufton, University of Strathclyde.

Email [email protected]

Kevin Howland, University of Kent

Email: [email protected]

Brent Irvine, Queen's University, Belfast

Email: [email protected]

Martin Quibell, Medivir.

Email: [email protected]

Sophie Gabriac , LGC (Teddington) Ltd, Teddington

Email: [email protected]

Robin Leatherbarrow, Imperial College London

Email: [email protected]

Roger Epton, Mayflower Worldwide Ltd

Email: [email protected]

Tony Johnson, Medivir

Email: [email protected]

John Wade, University of Melbourne

Email: [email protected]

Corinne Kay, GlaxoSmithKline

Email: [email protected]

Moharem El Gihani, Novabiochem

Email: [email protected]

John Fox, Alta Biosciences

Email: [email protected]

Co-opted:

Mike Gait, MRC Laboratory of Molecular Biology, Cambridge

Email: [email protected]

Brian Austen (Chairman) [email protected]

Brian is a Professor in Protein Science at St George�s Hospital Medical School in south London. With a background in protein/peptide chemistry, he has worked for a number of years into mechanisms of intracellular protein targeting. He was one of the first to use photo-crosslinking as a means of detecting translocator proteins in the endoplasmic reticulum membrane, and showed that the signal peptide binding subunit of mammalian signal recognition particle functions in bacteria. He has elucidated intracellular trafficking pathways of the amyloid precursor protein, thought to be causative in Alzheimer�s disease, and unravelled a hitherto mechanistic link between raised cholesterol levels and Alzheimer�s disease involving incresed deposition of amyloid. This work involved development of a sensitive assay to measure variants of b-amyloid in biological fluids with Ciphergen using affinity matrix ProteinArrays and mass spectrometry. In conjunction with CeNeS, he has developed inhibitors of b-amyloid fibril formation whichy prevent neurotoxicity. Other neurotoxic peptides, such as synuclein and Abri, known to produce fibrils, are also under study. The role of b-amyloid induced microglial-released inflammatory mediators (see Figure) in destroying neurones in the Alzheimer patients�s brain are under study, and in a collaborative project with Glaxo-Wellcome, cyclic hinge-loop peptides of IgG which bind the macrophage-specific Fc receptor and have potential as anti-inflammatory agents, have been synthesised. Brian is very much involved in a new innovative BSc degree in Biomedical Sciences at St George�s, which runs in parallel with the MBBS course.

El-Agnaf O, Sheridan J, Goodwin H & Austen BM (2000) Improved Solid-Phase syntheses of Amyloid Proteins associated with neurodegenerative Diseases. Peptide and Protein Letters. In press.

Davies H, Lomas and Austen B.(1999) Profiling of Amyloid b Peptide variants using Seldi ProteinChipTM Arrays. Biotechniques. 27, (6), 1258 � 1261.

Sheridan JM, Hayes, GM & Austen BM (1999) Solid-phase synthesis and cyclization of a large branched peptide from IgG Fc with affinity for Fcg RI. J Peptide Science. 5 (12) in press

Frears, ER, Stephens DJ. Walters CE, Davies H & Austen BM (1999) The role of cholesterol in the biosynthesis of b-amyloid. NeuroReport 10(8) 1699-1755.

Stephens DJ and Austen BM (1996) Metabolites of the ß-amyloid precursor protein generated by ß-secretase localise in the trans-Golgi network and late endosome. J Neuroscience Research. 45; 211-225.

Patel S & Austen BM (1996) Substitution of fifty four homologue (Ffh) in E. coli with mammalian 54-kDa protein if signal recognition particle. European J Biochem. 238; 760-768

Robinson, A., Kaderbhai, M.A. and Austen, B.M. (1987) Identification of Signal Sequence binding proteins integrated into the Rough Endoplasmic Reticulum membrane. Biochem. J. 242, 767-777.

John Deadman(Secretary) [email protected].

The Thrombosis research Institute is dedicated to the research of new therapies to be applied in the treatment of thrombotic disease. As well as being a multidisciplinary environment for scientists and clinicians to interact TRI is also a charity. It is now understood that thrombosis, the uncontrolled clotting of blood is involved in not only the pathology of myocardial infarction, stroke and unstable angina but also in tumour proliferation and, by the involvement of coagulation proteases, potentially in neuronal diseases such as Parkinsons. These disease processes are a major burden for society. Murray, C.J.L and Lopez, A.D. Science, 1996, 274, 740-743). The drug discovery section of the Thrombosis research Institute is involved in the design and development of new antithrombotic agents, especially inhibitors of the proteolytic enzymes involved in coagulation, as potential new medicinals and a 'tools' for biochemical research. It is salutatory to note that the cleavage of fibrinogen by the enzyme thrombin to give the critical, penultimate stage of clot formation was only characterised 50 years ago by B.Blomback.The chemistry section of the drug discovery team utilises modern techniques of combinatorial chemistry and paralell synthesis to screen for ligands of the target enzymes. Even for peptide libraries this can involve development of new chemistry (S.Merette, A.Burd and J.Deadman, Tet.Lett., 1999, 753). From these leads synthetic molecules with improved characteristics of selectivity and pharmacokinetics can be synthesised (J.Deadman et al.J.Med.Chem.,1995, 38, 1511). From a background in drug design, John has been involved in close interactions between the chemists and what they like to make, the biochemists who complain that we chemists make the wrong things and which way they want to assay the compounds and the pharmacologists, who want lots of everything that is soluble in water at pH7. The group uses high field 1 and 2D NMR, electrospray Mass spec and lots of HPLC in house to get what we want and rely on kind people in academia to support us with other techniques (take a bow all of you). The expertise of the biochemical group of Dr M.Scully at the TRI is critical to put a definitive figure on the activity of the compounds against both isolated enzymes and in the natural complexes. He is also critical (of 'you chemists') if the compounds are not pure enough!. To interpret the structural basis of the biological activity of these compounds computational modelling, in-house, and crystallography, through a valuable collaboration with Professor Dodsons' Protein structure group at the National Institute of Medical Research., (Skordalakes, E. et al Biochemistry, 1998, 37, 14420) london are being applied.

Dr Parvez Haris (Treasurer)[email protected]

After completing his PhD at the Royal Free Hospital School of Medicine under the supervision of Professor Dennis Chapman FRS in 1989, Dr Haris continued as a post-doctoral research fellow at the Royal Free until 1996. He took up a lectureship position in Biochemistry at De Montfort University, Leicester in 1996, and is currently a Senior Lecturer there. His research studies involve structure-function relationship in peptides, proteins and biomembranes. Particular emphasis is placed on understanding the interaction of peptides and proteins with phospholipid membranes. Diverse biophysical techniques are used to investigate how peptide and proteins interact with phospholipid bilayers and thereby attain their three-dimensional structure. Systems under investigation include ion-channel proteins, and a range of membrane active peptides. These research studies utilise a diverse range of biophysical techniques including FTIR, CD, NMR, DSC, X-ray scattering, Neutron diffraction etc. He also has interest in the area of biomaterials, and structure-stability studies of biotechnologically important proteins. He has published two books and over 60 papers in the field of proteins and biomembranes. Dr Haris is a member of the editorial board of the Biochemical Journal.

Van Dijk, A.A., Van Wijk, L.L., Van Vilet, A., Haris, P., Van Swieten, E., Tesser, G.I. and Robillard, G.T. (1997) Protein Science, 6, 637-648.

Brazier, S.P., Ramesh, B., Haris, P.I., Lee, D.C. and Srai, S.K. S. (1998) Biochem. J. 335, 375�380.

Haris, P.I. (1998) Bioscience Reports, 18, 299-312.

Haris, P.I. (1999) Pharm. Pharmacol. Commun. 5, 15-25.

Kelly, C.G., Younson, J.S., Hikmat, B.Y., Todryk, S.M., Czisch, M., Haris, P.I., Findall, F.R., Newby, C., Mallet, A.I., Ma, J.K-C., and Lehner, T. (1999) Nature Biotechnology, 17, 42-47.

Biomembrane Structures (ed. Haris, P.I. and Chapman,D.) 1998, IOS Press, Amsterdam.

New Biomedical Materials (ed. Haris, P.I. and Chapman, D.) 1998, IOS Press, Amsterdam.

Dr Mark Dufton. [email protected]

Mark belongs to the Organic Section of the Department of Pure and Applied Chemistry at the University of Strathclyde, and therefore approaches protein research very much at a molecular level, focussing in on the fine detail of conformation, reactivity and structural evolution. Attention is presently directed in 2 contrasting directions, namely:

1. The properties and mode of actions of venom proteins. Mark and coworker Dr Lois Anderson are characterising a multi-step enzyme pathway in cobra venom that is capable of generating reactive phenolic compounds rapidly from certain neuropeptides. At the moment, they are trying to unravel the complex mixture of spontaneous and enzyme-catalysed steps that lie at the end of the pathway and generate the phenolics from aromatic pyruvates. They suspect that this biosynthetic capability enhances the potency of other protein toxins in the venom, possibly by counteracting biochemical and behavioural defence measures mounted by the victim in response to the envenomation. In the long term, this research could benefit the wider use of proteins as drugs.

Anderson, L. & Dufton, M. (1998) "Oligopeptidases". In: Enzymes from Snake Venom (Bailey, G; Ed.). Alaken Inc. Fort Collins, Colorado. Chap.11.

Nucaro, E., Jodra, M., Russell, E., Anderson, L., Dennison, P. & Dufton , M. (1998) Conversion of tyrosine to phenolic derivatives by Taiwan cobra venom. Toxicon 36, 1173-1187

Dufton, M. & Harvey, A. (1998) Dendrotoxins. J.Toxicol: Toxin Rev. 17, 161-182

2. Theoretical analysis of protein sequence and 3D data as an aid to the deduction of functional site location and mechanism in protein molecules. As is now widely appreciated, protein structure databases are growing at a rate faster than that at which conventional experimental investigation is advancing our understanding of protein function and mechanism. Without that understanding, the majority of the information contained in the databases cannot be exploited for protein engineering. To provide a different way of tackling the problem, MJD is investigating the ways in which the structural and interactive chemistry of natural proteins has evolved during the history of life. For each characteristic fold type, his intention is to detect, map and grade the complicated 3D networks of internal selective relationships that have arisen between the component amino acid residues. Such maps are capable of revealing the locations of interactive sites on the protein surface and how a recognition event might translate into a conformational adjustment. Current work centres on protein folds as "learning devices" which maintain and adapt

sophisticated chemical "memories" in the face of continued internal and external change.

Pritchard, L. & Dufton, M. (2000) Do proteins learn to evolve? The Hopfield network as a basis for the understanding of protein evolution. J.Theor. Biol. In press.

Pritchard, L. & Dufton, M. (1999) Evolutionary trace analysis of the Kunitz/BPTI family of proteins. J.Mol.Biol. 285, 1589-1607

Cardle, L.& Dufton, M. (1997) Foci of amino acid residue conservation in the 3D structures of the Kunitz/BPTI proteinase inhibitors. Prot. Engng. 10, 131-136

Dr Kevin Howland - [email protected]

Kevin manages a core analytical biochemistry facility providing: protein sequencing, mass spectrometry, peptide synthesis, chromatography and secondary structure support to the Research School of Biosciences and external collaborators at the University of Kent. Previously he had spent 6 years at Pfizer Central Research in Sandwich where he had responsibility for their protein science facilities. Prior to working at Pfizer he headed the peptide synthesis facility at the ICRF in London where he worked for almost 4 years. His research interests include:

1. Novel applications of analytical techniques mainly to aid identification and characterisation of protein products although analysis of other biomolecules is also of interest.
2. Analysis of factors affecting protein productivity during cloning and subsequent adaptation to cell culture conditions.
3. Identification of novel substrates and development of new assay techniques for blood clotting factors.

Glaser, M., Howard, M.J., Howland, K., Powell, A.K., Rae, M.T., Wocadlo, S.,

Williamson, R.A., and Blower, P.J.

Structural characterisation and bioconjugation of an active ester containing oxorhenium(V) complex incorporating a thioether donor.

J. Chem. Soc. Dalton Trans., 1998, 3087-3092

Rae, M.T., Menzies, G.S., Howland, K. and Bramley, T.A.

Stimulation of specific binding of [3H]-progesterone to bovine luteal cell-surface membranes: specificity of digitonin.

Molecular And Cellular Endocrinology, 1999, 153, 57-69

Mullen, G.E.D., Fässler, T.F., Went, M.J., Howland, K., Stein, B., and Blower, P.J.

An investigation of C�S bond activation in transition metal crown thioether complexes using extended Hückel theory and electrospray mass spectrometry

J. Chem. Soc., Dalton Trans., 1999, 3759�3766

Dr Brent Irvine [email protected]

Since being appointed to a lectureship at Queen's University in 1980 Brent has been applicant or co-applicant on grant proposals that have brought in excess of �500,000 funding to the university. He has supervised a total of 10 postgraduate students and three postdoctoral research assistants. He has organised several colloquia at scientific meetings and was overall organiser for the Biochemical Society Meeting held in Queen's University on 14-17 September 1993. He ran a colloquium on "Neuropeptides" at this meeting and was later asked to edit a book on this topic, published in 1997 (Irvine, G.B. and Williams, C.H. (eds.) "Neuropeptide Protocols" Methods in Molecular Biology Vol. 73, pp. 386, Humana Press, Totowa, New Jersey, USA). He has a particular interest in size-exclusion HPLC of peptides and proteins.

Recent research interests relate mainly to neurodegenerative disease such as Alzheimer's and Parkinson's Diseases. Current projects concern the physicochemical properties of b-amyloid peptides, and properties and neurotoxicity of non-Ab component of Alzheimer's amyloid. Brent has a DENI-supported PhD student and an MPhil student, and is studying the physicochemical properties of peptides that aggregate to form fibrils and deposit as amyloid, with a view to understanding the nature of their interactions and toxicity to neurones.

Irvine, G.B. and Williams, C.H. (eds.) (1997) "Neuropeptide Protocols" Methods in Molecular Biology Vol. 73, pp. 386, Humana Press, Totowa, New Jersey, USA.

El-Agnaf, O.M.A., Bodles, A.M., Guthrie, D.J.S., Harriott, P. and Irvine, G.B. (1998) The N-terminal region of non-Ab component of Alzheimer�s Disease amyloid is responsible for its tendency to assume b-sheet and aggregate to form fibrils. Eur. J. Biochem. 258, 157-163.

El-Agnaf, O.M.A., Irvine, G.B., Fitzpatrick, G., Glass, K.W. and Guthrie, D.J.S. (1998) Comparative studies on peptides representing the so called tachykinin-like region of Alzheimer Ab peptide, Ab (25-35). Biochem. J. 336, 419-427.

Dr Martin Quibell [email protected]

Martin Graduated from Portsmouth in 1988 with a 1st BSc(Hons)in

Applied Chemistry. He completed hisPhD studies at the University of Birmingham (1988 - 1991) on substrate-based protease inhibitor design, with particular reference to the preparation of azapeptides as potential inhibitors of picornaviral 3C proteases(1). Post doctoral studies were performed as a research scientist in the Sheppard group at the MRC Laboratory of Molecular Biology (1991-1996), where he gained broad experience in many aspects of solid phase synthesis, with

particular focus on the preparation of 'difficult peptide' sequences (2) and segment assembly of small proteins (3). Martin joined Peptide Therapeutics, Cambridge (1996) as Section Head for combinatorial chemistry, with a main research focus in protease and kinase inhibitor design. He developed a new library synthesis and screening technology, the RAPiD system (4) for the elucidation of protease specificity and was promoted to Director of Medicinal Chemistry (1999) with responsibility for progressing research programmes towards potential clinical candidates.

C. J. Gray, M. Quibell, N. Baggett and T. Hammerle, Int. J. Pept. Prot. Res, 40, 1992, p351-362. 'Incorporation of azaglutamine residues into peptides synthesised by the ultra-high load solid (gel)-phase technique'.

M. Quibell and T. Johnson, 'Difficult Peptides' in 'Fmoc Solid Phase Peptide Synthesis - A Practical Approach' (Ed. W. C. Chan and P. D. White), Oxford University Press, 1999, p 115-135.

M. Quibell, L. C. Packman and T. Johnson, J. Am. Chem. Soc, 117, 1995, p 11656-11668. 'Synthesis of the 3-Repeat Region of Human Tau-3 by the Solid Phase Assembly of Backbone Amide- Protected Segments'.

M. Quibell, Innovations in Pharmaceutical Technology, vol 2, 1999, p16-21.

'The RAPiD approach to library design'.

Other members of the committee are:

Prof Roger Epton, Mayflower Press. [email protected],

Dr Tony Johnson, Peptide Therapeutics [email protected]

John Wade, University of Melbourne. [email protected]

Sophie Gabriac, LGC. [email protected]

Robin Leatherbarrow, Imperial College London. [email protected]

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