Elsevier

Tetrahedron

Volume 57, Issue 12, 17 March 2001, Pages 2247-2277
Tetrahedron

Tetrahedron report number 559
Synthetic peptide conjugates—tailor-made probes for the biology of protein modification and protein processing

https://doi.org/10.1016/S0040-4020(00)01115-7Get rights and content

With the help of synthetic peptide conjugates the effect of protein glycosylation and lipidation on protein structure, localization and function can be studied in molecular detail. The conjugation of pharmacophores provides tools that help in unravelling the physiological roles of protein degradation.

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Introduction

The development of methods that allow the chemical synthesis of peptides and small proteins is of utmost importance for the advancement of life science-oriented enterprises. Today, peptide synthesis has reached a level of maturity that gives non-chemists the opportunity to readily synthesize well-defined materials suitable for a systematic evaluation of structure–activity relationships. The degree of complexity that can be realized by routine synthesis, however, by no means matches that of naturally occurring proteins. The majority of proteins are post-translationally modified, reflecting the subtle mechanisms by which protein function can be regulated. Of the many types of protein modification possible, this review will focus on the synthesis and use of two very common methods, namely the attachment of carbohydrate and lipid groups to amino acid side chains. It will be demonstrated that with the help of these synthetic peptide conjugates, the effect of glycosylation and lipidation on protein structure, localization and function can be studied in molecular detail.

Synthetic peptide conjugates are of high utility not only for analysing but also for influencing biological processes. For example, the attachment of pharmacophoric groups to peptides furnishes conjugates that are invaluable tools for modern cell biology. This feature will be illustrated by describing how these peptide conjugates have helped in unravelling the physiological roles of proteasome-mediated protein degradation and of caspase-mediated proteolysis during apoptosis.

Section snippets

Glycopeptides

The most abundant post-translational modification is protein glycosylation, which introduces an enormous structural diversity to proteins. By the attachment of glycans protein structure and activity can be regulated.1 Glycoproteins are involved in biological recognition events such as cell adhesion, cell differentiation and infection.2., 3., 4., 5. Aberrant glycosylation is associated with various conditions such as autoimmune and infectious diseases and cancer. Since glycoproteins exist in

Lipopeptides

Two decades ago, the first prenylated polypeptide, Rhodotorucine A, the mating factor from the fungus Rhodospiridium toruloides, was discovered.81 The notion that entire proteins could be post-translationally modified, however, has only recently been realized. In one of the key experiments, the use of mevalonate biosynthesis inhibitors revealed that products of mevalonate metabolism other than cholesterol were essential for cell cycle progression.82., 83. It was soon observed that a metabolite

Apoptosis

In multicellular organisms, the constancy of cell number (homeostasis) is regulated by the rate of cell proliferation and cell death. Developmental biologists were the first to recognize that the controlled autodigestive process of apoptosis (programmed cell death) is a life-saving event for multicellular organisms.161., 162. Excess and old (erythrocytes, epidermal cells) or potentially dangerous (autoimmune T-cells, mildly injured cells) cells are regularly eliminated by activating their

Conclusion and outlook

The examples described in this review demonstrate that the recent improvements in the synthetic methodology have enabled the synthesis of a variety of modified peptides such as glycopeptides, lipopeptides and peptide pharmacophore conjugates. It is particularly encouraging that the degree of peptide conjugate complexity that can be accessed by current techniques meets the many needs of biological and medicinal research. The use of synthetic glycopeptides revealed that the attachment of

Oliver Seitz was born in Frankfurt, Germany, in 1966 and received his Diploma in chemistry from the University of Mainz in 1992. He obtained his Ph.D. there in 1995 under the supervision of Professor Horst Kunz developing a new linker for solid phase glycopeptide synthesis. In 1996 he worked as a postdoctoral fellow in the laboratories of Professor Chi-Huey Wong at the Scripps Research Institute in La Jolla, California. He returned to Germany in 1997 and started his work towards the

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      The CPE peptide is an alternative to the peptide thioester, and can be prepared by standard Fmoc (SPPS) because it contains no thioester moiety itself. Moreover, the autoactivating function of the CPE unit can be quenched by introducing a thiol blocking group in the Cys residue, which would prevent inter- and intramolecular ligation itself, and the direction of ligation at the N or C terminus could be controlled,25 thus providing a flexible ligation strategy for polypeptide synthesis using multi-component peptide building blocks. In this report, we provide a detailed description of such thioester formation and ligation using the CPE autoactivating unit.

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    Oliver Seitz was born in Frankfurt, Germany, in 1966 and received his Diploma in chemistry from the University of Mainz in 1992. He obtained his Ph.D. there in 1995 under the supervision of Professor Horst Kunz developing a new linker for solid phase glycopeptide synthesis. In 1996 he worked as a postdoctoral fellow in the laboratories of Professor Chi-Huey Wong at the Scripps Research Institute in La Jolla, California. He returned to Germany in 1997 and started his work towards the Habilitation under the chair of Professor Herbert Waldmann at the University of Karlsruhe. In 2000, he moved to the Max-Planck-Institut of Molecular Physiology in Dortmund where he leads a group in the Department of Chemical Biology and the Institute of Organic Chemistry at the University of Dortmund. His research interests include the synthesis and functionalization of biopolymers such as peptides, glycopeptides, nucleic acids and analogues for the further usage as biomolecular tools. Most recently he has been working on the development of new strategies for the functionalization of peptide nucleic acids.

    Ines Heinemann, born in Eckernförde, Germany, in 1971, studied chemistry and biology at the University of Kiel. In 1997 she received her Diploma in chemistry after working on the synthesis of macrocyclic musk odorants under the supervision of Professor W. Tochtermann. She obtained the Diploma in biology in 1998 with a thesis on proteins and protein complexes at the outer chloroplastic envelope membrane which she carried out in the group of Professor J. Soll. In 1998, she joined the group of Professor H. Waldmann in Karlsruhe to work on the synthesis and evaluation of lipidated peptides and proteins.

    Amos Mattes, born in 1972 in Strümpfelbach, Germany, studied chemistry at the universities of Kaiserslautern and Würzburg. At the Ecole Supérieure de Chimie Physique Electronique (CPE) in Lyon, France, he developed analogues of cyclophosphamide in 1996. The following year he finished his diploma in bioinorganic chemistry with a thesis on the C/Si bioisosterism of potential antimuscarinics in the group of Professor R. Tacke. In 1998 he commenced work on his Ph.D. thesis which he performs in the group of Oliver Seitz. His current research interest is focused on the synthesis of oligonucleotides and peptide nucleic acids and their use in template-directed reactions.

    Herbert Waldmann, born in 1957, received his Dr. rer. nat. in 1985 (Universität Mainz, H. Kunz). After postdoctoral studies (1985–1986, Harvard University, George Whitesides) and habilitation (1991, Universität Mainz) he accepted a professorship at the Universität Bonn in 1991. In 1993 he moved to the Universität Karlsruhe as Full Professor of Organic Chemistry. In 1999 he was appointed as Director at the Max-Planck-Institut of Molecular Physiology, Dortmund (Department of Chemical Biology) and as Full Professor of Biochemistry at the University of Dortmund. Herbert Waldmann has been the recipient of the Friedrich Weygand Award for the advancement of peptide chemistry, of the Carl Duisberg Award of the Gesellschaft Deutscher Chemiker and the Steinhofer Award of the Steinhofer Foundation. His current research interests include bioorganic chemistry and natural product synthesis as well as biocatalysis, stereoselective synthesis and combinatorial chemistry. A major focus of his research activities is on the combination of organic chemistry, biophysics and biology for the synthesis and biological evaluation of peptide and protein conjugates that are involved in biological signal transduction processes. Most recently syntheses of natural products and natural product derived compound libraries on polymeric supports have been investigated by the Waldmann group (see the home page for further information: www.mpi-dortmund.mpg.de).

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