Group Leader:

Prof. J.A. Robinson

Tel (01) 635 42 42

e-Mail: robinson@oci.unizh.ch mail to Prof. Robinson

Secretary:

Heike Götzmann

Tel (01) 635 42 40

e-Mail: heike.goetzmann@oci.unizh.ch

Scientific Staff:

Dr. Jan W. Vrijbloed - Oberassistent

Tel (01) 635 42 19

e-Mail: vrybloed@oci.unizh.ch mail to Dr. Vrijbloed

Lab. Staff:

Anneliese Meier (Lab. Technician, Tel (01) 635 41 96)

e-Mail: annelies@oci.unizh.ch mail to Anneliese Meier

Group Members:

OCI-Phonebook#Robinson

Research Topics Biological Chemistry Combinatorial Biomimetic Chemistry Computational Chemistry Enzymatic Reactions Molecular Recognition Mimetics of Proteins and Peptides Synthetic Vaccines

Research Interests of Prof. J. A. Robinson

The research interests of the group lie in the area of biological chemistry, in particular, the mechanisms of biological molecular recognition; the design of novel peptide and protein mimetics; synthetic vaccine design; combinatorial biomimetic chemistry and its application in drug and vaccine discovery; and the study of enzymes invovled in antibiotic biosynthesis.

In the area of macromolecular recognition we are studying the mechanisms that antibodies use to bind specific surface epitopes of protein antigens. Antibodies must evolve in a relatively short time period to bind surface epitopes of proteins. So the interest lies in determining which types of interactions are used by the immune system for this purpose, and what their relative importance is. Presently, we are studying antibodies that bind to the extracellular portion of the interferon gamma receptor. This cytokine receptor is present on many cell types in the hematopoietic system, and binds with high affinity to the immunostimulatory cytokineinterferon gamma. Our work involves structural studies of ligand-receptor and antibody-receptor complexes. We currently have X-ray crystal structures available to guide mutagenesis experiments. Structural and thermodynamic studies of mutant receptors and antibody fragments provide the basis for improving understanding of the mechanisms of biological recognition. The information and insights gained may be valuable in the design of molecules with novel recognition properties (see below).
Another interest lies in the design and synthesis of novel protein surface mimetics. Many proteins exert their biological activity through interactions involving relatively small regions of their exposed surfaces. Small synthetic molecules that mimic surface features of proteins are therefore of potential interest in the design of novel drug candidates, including synthetic vaccines. Short linear peptides are not ideal for this purpose, because of their inherent flexibility. To overcome this problem, we have designed novel templates to constrain peptide chains into biologically relevant secondary structures. We use NMR spectroscopy and MD simulations to study the structure and conformational properties of the mimetics we prepare. In one application, we have synthesized mimics of a conformational epitope on the malaria parasite Plasmodium falciparum, which may be of interest for the development of a synthetic malaria vaccine. In other work, we are exploring the use of combinatorial chemistry as a means to produce small libraries of protein surface mimetics.
The third area of interest is in the use of enzymes from secondary metabolism, as catalysts for the production of novel bio-active molecules. Presently, we are studying enzymes that are involved in the biosynthesis of the vancomycin family of glycopeptide antibiotics in Amycolatopsis orientalis. The enzymes of interest catalyze poorly understood, but highly interesting, cross-linking reactions during the biosynthesis of the peptidic part of the vancomycin molecule. The genes for these enzymes have been cloned and sequenced, and are now being used to produce the enzymes conveniently in bacteria such as E. coli. Synthetic peptide-like substrates are used to study the mechanisms of the enzymic reactions. Ultimately we hope to use these enzymes to produce novel peptidic molecules with antibacteial or antiviral activities.
Openings for new postgraduate students and post-doctoral coworkers arise each year. The research effort in the group is divided almost 50:50 between chemistry (largely synthesis) and biochemistry/molecular biology. New Ph.D. students must have interests in one of these areas, and have an appropriate qualification, which normally is a "Diplom" in Chemistry, or Biochemistry, or a relevant area of Biology. The "Diplom" is usually considered equivalent to a four year degree (e.g. M.Sc or similar) at UK or other European Universities. Post-doctoral coworkers should have completed a Ph.D. program in a relevant area. Those scientists that can bring their own financial support through a grant-awarding institution are, of course, particularly welcome.

Peptide and Protein Mimetics

Many proteins exert their biological activity through interactions involving relatively small regions of their exposed surfaces. Molecules that mimic these surface epitopes are therefore of great interest, since they may provide a means of mimicking the biological activity of the entire protein in a relatively small synthetic molecule.

 

Towards a Synthetic Malaria Vaccine

One potential application of protein epitope mimetics is in synthetic vaccine design. We are particularly interested in mimetics as the basis for a synthetic vaccine against the malaria parasite.
This work is conducted in collaboration with parasite biologists at the Swiss Tropical Institute and immunologists at the Swiss Vaccine and Serum Institute.

 

Combinatorial Biomimetic Chemistry

This is a new research interest in the group, which seeks to exploit the methods and tools we have developed in the design and synthesis of protein epitope mimetics. The aim is to create a technology platform for producing libraries of epitope mimetics using combinatorial chemistry methods.
This project is carried out in collaboration with the company Polyphor AG.

 

Mechanisms of Biological Molecular Recognition

The mechanisms used in Nature for biological macromolecular recognition are of fundamental interest. An understanding of these mechanisms may also be useful for the design of new molecules with interesting recognition properties. One ligand-receptor system currently under investigation is that for the cytokine interferon gamma.

 

Enzyme Chemistry

Here we are interested in enzymes from secondary metabolism, that are involved in the biosynthesis of the vancomycin family of glycopeptide antibiotics in Amycolatopsis orientalis. Ultimately, the plan is to use these enzymes to produce novel peptidic molecules with antibacterial and antiviral activities. This work is conducted within a larger project funded by the European Union, with participating groups in five EU countries.

The Research Interests of Prof. J. A. Robinson as PDF-document (80 kB)

Selected Publications

Dissection of the extracellular human interferon gamma receptor into two immunoglobulin-like domains. Production in an E. coli thioredoxin gene fusion expression system and recognition by neutralizing antibodies.
G. Williams, N. Ruegg, A. Birch, C. Weber, K. Hofstetter, J. A. Robinson, M. Aguet, G. Garotta, D. Schlatter and W. Huber.
Biochemistry 1995, 34, 1787-1797.

Synthesis of a type-VI beta-turn mimetic and its incorporation into a high affinity somatostatin receptor ligand.
D. Gramberg, C. Weber, J. Inglis and J. A. Robinson.
Helv. Chim. Acta. 1995, 78, 1588-1606.

Stabilization of type-I beta-turn conformations in peptides containing the NPNA-repeat motif of the Plasmodium falciparum circumsporozoite protein by substituting proline for (S)-alpha-methylproline.
C. Bisang, C. Weber, J. Inglis, C. A. Schiffer, W. F. van Gunsteren, I. Jelesarov, H. R. Bosshard and J. A. Robinson.
J. Amer. Chem. Soc. 1995, 117, 7904.

On the stereospecificity of the coenzyme-B12 dependent isobutyryl-CoA mutase reaction.
B. S. Moore, R. Eisenberg, C. Weber, A. Bridges, D. Nanz and J. A. Robinson.
J. Amer. Chem. Soc. 1995, 117, 11285-11291.

Cloning, sequencing, overexpression in Escherischia coli and inactivation of the valine dehydrogenase gene in the polyether antibiotic producer Streptomyces cinnamonensis.
A. Leiser, A. Birch and J. A. Robinson.
Gene 1996, 177, 217-222.

Production and characterization of anti-human interferon gamma receptor antibody fragments that inhibit cytokine binding to the receptor.
A. Bridges, F. Stuart, J. Spath, S. Lang, C. Henke, ch, J. A. Robinson.
Protein Engineering 1996, 9, 365-370.

Protein loop mimetics. A diketopiperazine-based template to stabilize loop conformations in cyclic peptides containing the NPNA- and RGD-motifs.
C. Bisang, C. Weber and J. A. Robinson.
Helv. Chim. Acta. 1996, 79, 1825-1842.

A template for the solid-phase synthesis of conformationally restricted protein loop mimetics.
F. Emery, C. Bisang, M. Favre, L. Jiang and J. A. Robinson.
J. Chem. Soc., Chem. Comm. 1996, 2155-6.

A tricyclic template derived from (2S, 4S)-4-hydroxyproline and its incorporation into a cyclic protein loop mimetic containing a NPNA-motif.
R. Beeli, M. Steger, and J. A. Robinson.
Helv. Chim. Acta. 1996, 79, 2235-2248.

Dynamical studies of peptide motifs in the Plasmodium falciparum circumsporozoite surface protein by restrained und unrestrained MD simulations.
A. P. Nanzer, A. E. Torda, C. Bisang, C. Weber, J. A. Robinson and W. F. van Gunsteren.
J. Mol. Biol. 1997, 273, 882-897.

Synthesis of a novel tricyclic dipeptide template and its incorporation into a cyclic peptide mimetic containing an NPNA motif.
M. E. Pfeifer, A. Linden and J. A. Robinson.
Helv. Chim. Acta. 1997, 80, 1513-1527.

Cloning, sequencing, expression and insertional inactivation of the gene for the large subunit of the coenzyme B12-dependent isobutyryl-CoA mutase from Streptomyces cinnamonensis.
K. Zerbe-Burkhardt, A. Ratnatilleke, N. Philippon, A. Birch, A. Leiser, J. W. Vrijbloed, D. Hess, P. Hunziker, J. A. Robinson.
J. Biol. Chem. 1998, 273, 6508-6517.

Synthesis, conformational properties, and immunogenicity of a cyclic template-bound peptide mimetic containing an NPNA motif from the circumsporozoite protein of Plasmodium falciparum.
C. Bisang, L. Jiang, E. Freund, F. Emery, C. Bauch, H. Matile, G. Pluschke and J. A. Robinson.
J. Am. Chem. Soc. 1998, 120, 7439-7449.

Stabilization of a beta-hairpin conformation in a cyclic peptide using the templating effect of a heterochiral diproline unit.
J. Spath, F. Stuart, L. Jiang and J. A. Robinson.
Helv. Chim. Acta. 1998, 81, 1726-1738.

Stabilisation of beta-hairpin conformations in a protein surface mimetic using a bicyclic template derived from (2S,3R,4R)-diaminoproline.
M. E. Pfeifer and J. A. Robinson.
J. Chem. Soc., Chem. Comm. 1998, 1977-1978.

On the importance of being aromatic at an antibody-protein antigen interface: Mutagenesis of the extracellular interferon gamma receptor and recognition by the neutralizing antibody A6. K. Hofstaedter, f. Stuart, L. Jiang, J. W. Vrijbloed and J. A. Robinson.
J. Mol. Biol. 1999, 285, 805-815.

Structural mimicry of canonical conformations in antibody hypervariable loops using cyclic peptides containing a heterochiral diproline template.
M. Favre, K. Moehle, L. Jiang, B. Pfeiffer and J. A. Robinson.
J. Am. Chem. Soc. 1999, 121, 2679-2685.

Solid-phase synthesis of a putative heptapeptide intermediate in vancomycin biosynthesis.
E. Freund and J. A. Robinson.
J. Chem. Soc., Chem. Comm. 1999, 2509-2510.

Cloning and sequencing of the coenzyme B12-binding domain of isobutyryl-CoA mutase from Streptomyces cinnamonensis, reconstitution of mutase activity, and characterization of the recombinant enzyme produced in Escherichia coli.
A. Ratnatilleke, J. W. Vrijbloed and J. A. Robinson.
J. Biol. Chem. 1999, 274, 31679-31685.

Synthesis and solution conformation of beta-hairpin mimetics utilizing a template derived from (2S,3R,4R)-diaminoproline.
M. E. Pfeifer, K. Moehle, A. Linden and J. A. Robinson.
Helv. Chem. Acta. 2000, 83, 444-464.

The design, synthesis and conformation of some new beta-hairpin mimetics: Novel reagents for drug and vaccine discovery.
J. A. Robinson.
Syn. Lett. 2000, 429-441.

Solid-phase synthesis using (allyloxy)carbonyl(Alloc) chemistry of a putative intermediate in vancomycin biosynthesis containing m-chloro-3-hydroxytyrosine.
E. Freund, F. Vitali, A. Linden and J. A. Robinson.
Helv. Chim. Acta. 2000, 83, 2572-2579.

Combinatorial biomimetic chemistry: Parallel synthesis of a small library of ß-hairpin mimetics based on loop-III from human platelet-derived growth factor
B. L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht and J. A. Robinson.
Helv. Chim. Acta. 2000, 83, 3097-3112.

Analysis of antibody A6 binding to the extracellular interferon g receptor a-chain by alanine-scanning mutagenesis and random mutagenesis with phage display.
S. Lang, J. Xu, F. Stuart, R. Thomas, J. W. Vrijbloed and J. A. Robinson.
Biochemistry 2000, 39, 15674-15685.

Exploiting Conformationally Constrained Peptidomimetics and an Efficient Human-Compatible Delivery System in Synthetic Vaccine Design.
R. Moreno, L. Jiang, K. Möhle, R. Zurbriggen, R. Glück, J.A. Robinson, G. Pluschke
ChemBioChem 2001, 2 , 838-843.

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