Peptide combinatorial library design

SI Cho, W Zheng, A Tropsha. Rational combinatorial library design 2. Rational design of targeted combinatorial peptide libraries using chemical similarity probe and the inverse QSAR approaches. J Chem Inf Comput Sci 38 259-268, 1998. 

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. 

Cho, S.J., Zheng, W. andTropsha, A. Rational Combinatorial Library Design. 2. Rational Design of Targeted Combinatorial Peptide libraries using chemical similarity probe and inverse QSARapproaches. J. Chem. Inf. Comput. Sci., 1998,38,259-268. 

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. 

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

Bicker KL, Sun J, Lavigne JJ, Thompson PR (2011) Boronic acid functionalized peptidyl synthetic lectins combinatorial library design, peptide sequencing, and selective glycoprotein recognition. ACS Comb Sci 13 232-243... 

Koppel, G., Dodds, C., Houchins, B., Hunden, D., Johnson, D., Owens, R., Chaney, M., Usdin, T, Hoffman, B. and Brownstein, M., Use of peptide combinatorial libraries in drug design The indication of a potent serotonin reuptake inhibitor derived from a tripeptide cassette library, Chem. Biol., 2(1995) 483-487. 

Dynamic combinatorial libraries (DCLs) are continuously interconverting libraries that evenmally evolve to an equilibrium distribution [61-65]. This approach has been used successfully in the discovery of stable supramolecular assemblies from mixtures. Due to the nearly endless possible peptide sequences that can potentially be synthesised, the DCL approach is attractive for the identification of supramolecular peptide interactions. Indeed, disulfide exchange between cysteine residues has been explored for this purpose [66, 67] as has peptide-metal binding [68]. We have recently demonstrated protease-catalysed amide exchange in this context, which allows for the evolution of the self-assembled peptide structures, and will therefore allow exploration of peptide sequence space for biomaterials design. 

Another use for combinatorial libraries has been the screening of peptides for antimicrobrial properties. In this case, the design of the library is based on antimicrobial peptides found in nature. A combinatorial synthesis is used to find alternative unnatural amino acids expected to mimic the antimicrobial properties.23 Peptide libraries also have been used to find compounds that could bind the lytic peptide mellitin.24 The library was synthesized in solution phase, purified, and evaluated using time-of-flight mass spectrometry (TOF-MS). The sequences determined to bind to mellitin contained hydrophobic pairs. By binding to mellitin, they were able to prevent the cell-surface mellitin interaction. This is an example of a peptide library able to afford compounds that interact with other small peptides without having to find an interacting protein first. 

Youngquist, R. S. Fuentes, G. R. Lacey, M. E Keough, T. 1995. Generation and screening of combinatorial peptide libraries designed for rapid screening by mass spectrometry. J. Am. Chem. Soc., 117, 3900-3905. 

Outline a design for a combinatorial synthesis for the formation of a combinatorial library of nine compounds with the general formula B using the Furka mix and split method. Outline any essential practical details. Details of the chemistry of peptide link formation are not required it is sufficient to say that it is formed. 

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