Solid-phase peptide synthesis combinatorial library

Amino Acids, Chemical Properties of Click Peptides, Design and Application of Peptide Combinatorial Libraries Solid-Phase Synthesis of Biomolecules... 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

Beausoleil, E., Truong, K.T., Kirshenbaum, K., and Zuckermann, R.N. Influence of monomer structural elements in hydrophilic peptoids. In Innovations and Perspectives in Solid Phase Synthesis and Combinatorial Libraries Peptides, Proteins, and Nucleic Acids, R. Epton (Ed.), 2001, Mayflower Scientific Press Kingswin-ford, UK, pp. 239-242. 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

In general, solid-phase synthesis, rather than solution-phase synthesis, can be the preferred method for the generation of combinatorial libraries because of the greater abihty to automate a solid-phase protocol, primarily due to the use of excess reagents in solution to effect cleaner reactions and to the ease of workup by simple filtration. The solid-phase method of peptide synthesis has had many notable successes. However, the preparation of peptides containing more than 20 amino acids in length using the solid-phase technique often causes major problems in that very extensive purification of the final product is needed. 

NMR spectroscopy has been proposed as a versatile tool for the analysis of complex mixtures, combinatorial libraries, and heterogeneous samples, such as peptides bound to resins during solid-phase synthesis. 

Automated synthesis of peptide and oligonucleotide libraries was initiated about 10 years ago [4], Within the last three years, there has been much attention focused on the generation of combinatorial libraries of small molecules. As with biopolymers, the use of solid resin support was central to the advance of this field. In solid-phase synthesis, one of the reactants is covalently bound to the solid support and an excess of the other reactants may be used in each step to drive reactions to completion. Purification of the intermediates and final product is easily achieved through extensive washing of the resin after each chemical step. For the purpose of high throughput synthesis, cleavage of the final... 

Besides classical resin beads, other polymeric carriers were also used for the synthesis ofpeptide libraries in various formats. Poly aery late-grafted polypropylene pins were used for the synthesis of the first combinatorial chemical library [1,2], This type of support continues to be heavily used in multiple peptide [27] and non-peptide [28] library synthesis. Cellulose paper, originally used by Frank et al. as a solid-phase support for oligodeoxy-ribonucleotide synthesis [29], has also been used as the support for multiple SPOT synthesis of peptide libraries [30,31], Polystyrene-grafted polyethylene film (PS-PE) may also be used in combinatorial peptide library synthesis [32], The specific feature of the membrane type of carrier is its dividability. This feature has been used for the synthesis of libraries with a nonstatistical distribution of library members, where no compound is missing and none is represented more than once [33],... 

Saneii, H. H. and Shannon, J. D. (1994) Fully automated solid phase synthesis of combinatorial libraries on the peptide librarian. In Innovation and Perspectives in Solid Phase Synthesis (Epton, R., ed.), Intercept, Andover, UK, pp. 335-338. 

The ease, simplicity, and repetitive nature of solid-phase synthesis led to the development of automated synthesizers (Section 4.3.6). In addition, the advent of solid-phase peptide synthesis laid the groundwork for the development of combinatorial synthesis of peptide libraries that are now being used for the discovery of lead analogues for drug discovery (Section 4.3.7)... 

Han, Y. Vagner, J. Barany, G., In Innovation and Perspectives in Solid Phase Synthesis and Combinatorial Libraries Peptides, Proteins and Nocleic Acids, Small Molecole Organic Chemical Diversity, 1996, Epton, R., Ed. Mayflower Birmingham, UK, (19%) pp 385-388. 

The principal difference between the synthesis of individual peptides and peptide libraries is that mixtures of amino acids, rather than individual amino acids, are incorporated into selected or all positions of the sequence of peptide libraries. However, all current peptide chemistry strategies can be used for the synthesis of peptide libraries. In general, library synthesis requires greater emphasis on simplicity and reproducibility of the synthesis process. Although soluble supports have also been used for peptide library synthesis,the majority of methods used to synthesize peptide combinatorial libraries utilize Merrifield s concept of solid-phase synthesis,which is based on the sequential assembly of peptides after covalent attachment of the C-terminal amino acid to a polymeric solid support. This enables the excess of reagents to be removed by simple wash and filtration processes, and avoids the... 

Solid-phase synthesis of peptides was pioneered by Bruce Merrifield in the early 1960s. This work, for which he won the Nobel Prize in 1984, set in motion the modern approach to drug discovery called combinatorial chemistry. Through combinatorial chemistry, millions of compounds are generated by the synthesis of libraries on solid supports and screened for therapeutic activity by high-throughput assays. The importance of this work is attested by the numerous combinatorial research units that are now an integral part of most major pharmaceutical companies. 

Products/technologies PL sells a range of combinatorial chemistry resins consisting of polystyrene resins with chloromethyl functionality (PL-CMS) for use in solid phase synthesis of peptides, small-molecule libraries, and other... 

Reported applications of the technique to combinatorial syntheses include libraries of peptides ([69,71,72]), 4-amino-benzenesulfonamides ([69,71,72]), and peptidomimetics (poly-a-aza-amino acids or azatides, [69,71,73]). The latter synthesis also illustrates one of the advantages of the soluble polymer approach over solid-phase synthesis, namely. 

Recently, Fmoc-N-protected (3-amino acid synthons have been prepared and used for the synthesis of (3-peptides on solid phase [103]. This methodology facilitates enormously the search for new bioactive compounds, above all through the generation of combinatorial (3-peptide libraries. In this context, (3-amino acids have been used as building blocks for RGD cyclic peptides and for the synthesis of an inhibitor of human cathepsin L, previously identified by screening and deconvolution of pentapeptide amide collections [104,105]. 

This mild procedure for the solid-phase synthesis of peptides containing sterically hindered residues can be easily extended to generate combinatorial libraries of unnatural peptides, which may display biological properties superior to those of natural counterparts. 

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