Jutta Eichler

Generation and utilization of synthetic combinatorial libraries

The use of combinatorial chemistry is fundamentally changing the pace and scope of basic research and drug discovery. Since the introduction of synthetic peptide libraries several years ago, combinatorial chemistry has proven to be a powerful tool for the generation of immense molecular diversities of peptides, peptidomimetics and new organic compounds. This article briefly reviews methods for the generation and application of combinatorial libraries, with particular emphasis on soluble synthetic combinatorial libraries. The utility of these molecular diversities for basic research and drug discovery has been demonstrated through the identification of numerous highly active compounds such as antigenic peptides, receptor ligands, antimicrobial compounds and enzyme inhibitors.

Novel α-glucosidase inhibitors identified using multiple cyclic peptide combinatorial libraries

SummaryTwenty-six cyclic synthetic peptide combinatorial libraries (disulfides and lactams) of varying size and composition, representing 6.8 × 103 to 4.7 × 107 individual peptides, were synthesized along with their respective linear analogs. One of the hexapeptide lactam libraries (cyclo[xXxXxN]) was found to have significant α-glucosidase inhibitory activity. This library was carried through an iterative process of synthesis and screening, during which all of the five mixture positions (x and X) were successively defined. As the result of this process, potent and selective a-glucosidase inhibitors were identified.

Libraries from libraries: Generation and comparison of screening profiles

SummaryA positional scanning tetrapeptide library was chemically modified through alkylation and/or reduction of the amide bonds, thus generating three new combinatorial libraries with physico-chemical properties very different from the parent peptide library (‘libraries from libraries’). Specific results were obtained with each of these libraries upon screening in κ-opioid receptor binding and microdilution antimicrobial assays, illustrating the potential of the ‘libraries from libraries’ concept for the efficient generation of a variety of chemically diverse combinatorial libraries.