Functional Synthetic Receptors - Hardcover

Hardcover

ISBN 10: 3527306552 ISBN 13: 9783527306558

Verlag: Wiley-VCH, 2005

Inhaltsangabe

A timely overview of this rapidly-expanding topic, covering the most important classes of compounds and incorporating the latest literature. With its application-oriented approach, this book is the first to emphasize current and potential applications, extending to such fields as materials science, bioorganic chemistry, medicinal chemistry, and organic synthesis. In the biological context in particular, the book clarifies which receptor systems work well in water or better under physiological conditions.
From the contents:
* Amino Acid, Peptid and Protein Receptors
* Carbohydrate Receptors
* Ammonium, Amidinium and Guanidinium Receptors
* Anion Receptors
* Molecular Capsules and Self Assembly
* Dynamic Combinatorial Libraries based on Molecular Recognition
* Molecular Machines
* Self-Replication
Aimed at graduate students and specialists in the field, this is also of interest to pharmaceutical companies involved in drug design, as well as chemical companies with a polymer or nanotechnology group. In addition, analytical companies working on the advanced equipment covered here will find stimulating new applications.

Über diesen Titel

Über die Autorin bzw. den Autor

Thomas Schrader is Professor of Organic Chemistry at the University of Marburg. He studied chemistry and obtained his PhD in 1988 under W. Steglich at the Friedrich-Wilhelms-University of Bonn. After a postdoctorate stay at Princeton University under E.C. Taylor on total synthesis of antitumor agents, he gained his lecturing qualification at the University of Düsseldorf. In 2000 he joined the University of Marburg as associate professor. His research focuses on bioorganic aspects of supramolecular systems, optimizing and multiplying new binding motifs for characteristic structural features in biomolecules - a concept that leads to artificial receptor molecules capable of specifically interfering with biological processes. Applications include biosensors, drugs countering protein misfolding and tweezers for protein assembly. Professor Schrader is the holder of the Bredereck-symposium prize in bioorganic chemistry (2001).
 
Andrew D. Hamilton received his PhD from Cambridge University in 1980, and the following year carried out his postdoc research at Université Louis Pasteur, Strasbourg. Between 1981 and 1988 he was Assistant Professor for Chemistry at Princeton University, thereafter Associate Professor until 1992, when he became Full Professor at the University of Pittsburgh, a post he held until 1997. Since 1997 he has been Irénée duPont Professor of Chemistry and, since 1998, Professor of Molecular Biophysics and Biochemistry at Yale University. Here he held the Chair of the Chemistry Department between 1999 and 2003, and has been Deputy Provost for Science and Technology since 2003. Professor Hamilton lectures at several universities in the USA.

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Functional Synthetic Receptors

John Wiley & Sons

Copyright © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
All right reserved.
ISBN: 978-3-527-30655-8

Chapter One

Artificial (Pseudo)peptides for Molecular Recognition and Catalysis

Leonard J. Prins and Paolo Scrimin

1.1 Introduction

This chapter focuses on recognition and catalytic processes in which artificial (pseudo) peptide sequences, which can be very short, play a decisive role. The enormous amount of literature related to this topic is far beyond the scope of a single chapter, and, therefore, we intend to emphasize concepts and breakthroughs by using representative examples. Obviously, the reason for the interest in the role of (pseudo)peptides in molecular recognition and catalysis is the fact that polypeptides, e.g. proteins, play a crucial role in practically all biologically relevant processes. An incredible number of recognition events is of key importance for the occurrence of life. The origin of biological recognition is the tertiary structure of proteins, which is marvelously determined by conformationally well-defined secondary structures such as [alpha]-helices, -sheets, coiled coils, etc. These locally structured units give order to the overall system, positioning functional groups precisely in three-dimensional space, thus creating an active site where recognition takes place. Molecular recognition is especially crucial in the functioning of enzymes. To accomplish its powerful tasks an enzyme first needs to recognize the substrate and, subsequently, in the course of its chemical transformation, also the intermediate transition state that lies on the reaction pathway toward the product. These impressive results in Nature form an almost infinite source of inspiration for the chemist, not only to mimic natural functions but also to modify them and apply them in unnatural situations.

In this chapter we will discuss advances that have been made in our learning process from Nature and, more specifically, show how chemists are able to mimic natural functions using artificial synthetic molecules. First, we will focus on the biomolecular recognition of oligonucleotides (DNA/RNA) and protein surfaces by artificial oligopeptides. Next, we will show that chemists have learned to control the secondary structure of (pseudo)peptides and that specific (catalytic) functions can be introduced at will. Finally, we will conclude with a brief overview of the selection of (pseudo)peptide catalysts by a combinatorial approach.

1.2 Recognition of Biological Targets by Pseudo-peptides

1.2.1 Introduction

In all organisms, nucleic acids are responsible for the storage and transfer of genetic information. With the aim of curing gene-originated diseases, artificial molecules that can interact with DNA and RNA are of utmost interest. In this section we will discuss the current state of two major classes of pseudo-peptides that are currently under intense investigation - polyamides that bind in the minor groove of DNA and peptide nucleic acids (PNA). Both classes of compounds are inspired by naturally occurring analogs. The high synthetic accessibility and the ease with which chemical functionality can be introduced illustrate the high potential of artificial pseudo-peptides. In addition, their high biostability has enabled successful applications in both in-vitro and in-vivo studies. The limiting properties of these compounds will also be addressed.

Another way of interfering with biological processes is to obstruct the activity of proteins themselves. Pseudo-peptides that inhibit the formation of protein-protein complexes via competitive binding to the dimerization interface will be discussed. Selected examples will be given that clearly illustrate the strong increase in activity when amino acids present in a wild-type peptide sequence are replaced by artificial amino acids.

1.2.2 Polyamides as Sequence-specif ic DNA-minor-groove Binders

The discovery of the mode of interaction between the natural compounds distamycin and netropsin and the minor groove of DNA has been the impetus for the development of a set of chemical rules that determine how the minor groove of DNA can be addressed sequence-specifically. NMR and X-ray spectroscopy showed that distamycin binds to A,T-tracts 4 to 5 base pairs in length either in a 1:1 or 2:1 fashion, depending on the concentration (Fig. 1.1). It was then immediately realized by the groups of Dickerson, Lown, and Dervan that the minor groove of DNA is chemically addressable and, importantly, that chemical modifications of the natural compounds should, in theory, provide an entry to complementary molecules for each desirable sequence.

1.2.2.1 Pairing Rules

The minor groove of DNA is chemically characterized by several properties. First, the specific positions of hydrogen-bond donor and acceptor sites on each Watson-Crick base pair, as depicted schematically in Fig. 1.2. Next, the molecular shape of the minor groove in terms of specific steric size, such as the exocyclic N[H.sub.2] guanine. Finally, an important property is the curvature of the double stranded DNA helix. Having these properties as a guideline, Dervan and coworkers have developed a series of five-membered heterocycles that pairwise can recognize each of the four base pairs. These couples and their binding modes are schematically depicted in Fig. 1.3. To gain selectivity for a G,C over an A,T base pair, the pyrrole ring (Py) was substituted by an imidazole (Im), which forms an additional hydrogen-bond with the exocyclic N[H.sub.2] of guanine, as confirmed by crystal structure analysis. In addition, replacement of the pyrrole CH for an N eliminates the steric clash of pyrrole and the exocyclic N[H.sub.2] of guanine. The presence of an additional hydrogen-bond acceptor on thymine residues stimulated the synthesis of the N-methyl-3-hydroxypyrrole (Hp) monomer, which contains an additional hydrogen-bond donor. Also, in this case, the complementary molecular shape between the cleft imposed by the thymine-O2 and the adenine-C2 and the bumpy -OH are important.

The selective binding to T,A over A,T base pairs (and, similarly, G,C over C,G) originates from the antiparallel binding of two polyamide strands in the minor groove of DNA. A key NMR spectroscopy study confirmed that an ImPyPy polyamide bound antiparallel in a 2:1 fashion to a 5'-WGWCW-3' sequence (W = A or T) with the polyamide oriented N[right arrow]C with respect to the 5'[right arrow]3' direction of the adjacent DNA strand.

Recently, the repertoire of the heterocycles used (Py, Im, and Hp) has been expanded to novel structures based on pyrazole, thiophene, and furan, to increase binding specificity and stability (the Hp monomer has limited stability in the presence of free acid or radicals). In addition, benzimidazole-based monomers (Ip and Hz) were incorporated in polyamides as alternatives for the dimeric subunits PyIm and PyHp, respectively. DNase I footprinting revealed functionally similar behavior with regard to the parent compounds containing exclusively Py, Im, and Hp monomers. An important advantage is the chemical robustness of the benzimidazole monomer Hz relative to Hp.

1.2.2.2 Binding Affinity and Selectivity

The ternary complex composed of two three-ring structures, such as distamycin, and DNA is rather modest, for entropic reasons and because of the low number of hydrogen bonds involved. In an important step forward towards artificial DNA binders that can effectively compete with DNA-binding proteins, the carboxyl and amino...

Details zur Ausgabe

• Verlag: Wiley-VCH
• Erscheinungsdatum: 2005
• Sprache: Englisch
• ISBN 10: 3527306552
• ISBN 13: 9783527306558
• Einband: Gebundene Ausgabe
• Auflage: 1
• Anzahl der Seiten: 440
• Herausgeber: Schrader Thomas, Hamilton Andrew D.
• Kontakt zum Hersteller: Wiley-VCH GmbH; product_safety@wiley.com; ; Boschstrasse 12; Weinheim; 69469; Deutschland