Peptide combinatorial library development

It is important to further develop the concept of structure-activity relationships to precisely define the structural requirements of glutathione action. Thus, this section introduces the design, synthesis, and screening of a peptide combinatorial library to obtain multiple glutathione analogs. Combinatorial libraries will be composed of mixtures of peptides (consisting of natural or noncoded amino acids) on solid support. After cleavage from the resin, the mixtures of the peptides will be screened directly in different specific assays. 

Array-Based Techniques for Glycans Development and Applications Peptide Combinatorial Libraries Transcript Profiling Receptor-Ligand Interactions... 

Solid phase attachment of histidine-containing peptides by anchoring the imidazole ring to trityl resins has been developed for combinatorial library preparation of diketopiperazines <99TL809>. Histidine, histamine, and urocanic acid are edl imidazole-containing molecules that have been attached to a trityl-type resin to allow their application to combinatorial chemistry <99TL2825>. 

Synthetic combinatorial chemistry approaches have created a vast new source of molecular diversity for the potential identification of lead compounds. This revolutionary field enables hundreds to thousands of times more compounds to be synthesized and screened in shorter periods of time relative to traditional approaches. In particular, novel antibacterials and/or antifungals as well as inhibitory peptides of either HIV proteases or HIV integrase proteins13 were identified following the screening of synthetic combinatorial libraries (SCLs). As described below, SCLs have been used by this laboratory to develop antimicrobial and antifungal compounds, as well as novel treatments for HIV infection. 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

It is in the realm of very large combinatorial libraries that selection rather than screening gains crucial importance. As the focus shifts from randomizing an eight-residue peptide to a 100 amino acid protein (the typical size of a small functional domain, for example a chorismate mutase domain), the number of sequence permutations rises to an astronomical 20100. The ability to assay even a tiny fraction of this sequence space in directed molecular evolution experiments demands selection, even though initial development of an appropriate system may be considerably more involved than the setup of a screening procedure. 

One key aspecf of applicafions of combinatorial libraries in chemical biology is fhe mapping of subsfrafe specificities for enzymes. Alfhough the early studies that use peptide libraries were focused on studying antibody epitopes (12), the substrate mapping for enzymes that transform peptides and the development of molecular probes found widespread interest. 

The OBOC combinatorial library method is highly versatile and economical. It also is a form of chemical microarrays. Many investigators successfully have applied the on-bead screening methods in their research. The solution-phase and cell-based assays for OBOC libraries, however, are much less developed and have been applied successfully in only a few laboratories. A need exists to develop robust methods that allow investigators to screen routinely huge OBOC releasable peptide or chemical libraries (e.g., 200,000 compounds) with multiparametric... 

Obataya, I. Nakamura, C. Enomoto, H. Hoshino, T. Nakamura, N. Miyake, 1., Development of a herbicide biosensor using a peptide receptor screened from a combinatorial library. J. Mol. Catal. B Enzym 2004, 28, 265-271... 

Profile TPIMS is a nonprofit biomedical research institute focused on the development of combinatorial chemistry techniques that can be applied to all compound types. It was founded in 1988 to continue earlier research begun at The Scripps Research Institute in La Jolla, California, and in 1989 it began its research activities. Less than one year after beginning its operations, TPIMS scientists had developed a method for synthesizing and screening combinatorial libraries of tens of millions of peptides and other nonpeptide compounds. As a result of this early research, TPIMS became an internationally recognized research center in the field of molecular diversity and combinatorial chemistry. Research is funded by the National Institutes of Health, the National Science Foundation, the U.S. Army, and by a variety of pharmaceutical companies. 

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