High-throughput peptide synthesis

The use of QSAR descriptors for prediction and understanding of the activity of antimicrobial peptides has previously been limited to comparisons between peptides that differ in only a small number of amino acids. This has been primarily due to the cost and difficulty of producing large numbers of peptides as well as the cost of assaying their activity. However, with the recent advance in high-throughput peptide synthesis technique in combination with rapid assay of activity with the luminescence-based assay, robust amounts of data have begun to be available (35). 

The methodologies of high-throughput peptide synthesis are overviewed and discussed. Particular focus is given to the techniques applicable to laboratories with a limited budget. Automated solutions for synthetic problems are also discussed. 

This chapter does not follow the usual format of this series rather, it provides the reader with a general overview of techniques available for manual and automated high-throughput peptide synthesis. We were trying to be more specific in the description of techniques with which we are familiar, and that we believe are relevant for scientists in laboratories tasked to produce large numbers of peptides. In the case of automated synthesizers, we attempted to point out the potential problems that the user of a particular machine may face after the eventual purchase of the instrument—and that will definitely not be mentioned by the sales agent. 

Key Words Screening high-throughput SPOT synthesis cellulose luminescence Pseudomonas aeruginosa, QSAR antimicrobial antibacterial peptide machine learning artificial neural networks. 

Golebiowski, A., Klopfenstein, S. R., Chen, J. J., Shao, X. Solid supported high-throughput organic synthesis of peptide 3-turn mimetics via tandem Petasis reaction/diketopiperazine formation. Tetrahedron Lett. 2000,41,4841-4844. 

High throughput methods have increased our capacity for appropriate candidate compounds selection and also for developing libraries of novel compounds from which such candidates can be selected. Chapter 7 discusses the use of solid-phase synthesis for the high throughput production of peptides and other small molecules. In addition, as discussed in Chapter 6 on peptidomimetics, the swift production of novel leads holds considerable promise for future discovery of novel therapeutic agents. 

In recent years, developments in high-throughput screening inspired many pharmaceutical companies to focus and rely on combinatorial chemistry, especially massive parallel synthesis, to find new lead structures. The employed chemistry is often simple and the concept depends on sheer numbers for success. The main research areas were heterocyclic and peptide chemistry, and the resulting structures often lacked complexity and diversity, and most importantly the chance to utilize the evolutionary advantage of natural products with their privileged structures. 

During the early part of this decade, most efforts in high-throughput synthesis utilized solid phase organic synthesis (SPOS) techniques.1-3 SPOS was a natural outgrowth of earlier methods used to synthesize peptides and oligonucleotides.4 This method has several advantages over traditional solution-phase synthesis ... 

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