Abstract
Synthetic combinatorial libraries (SCLs) consisting of millions of compounds are proving to be a powerful source for the identification of novel biologically active compounds (see ref. 1–3). Individual compounds having potent biological activities can now be rapidly identified from pools containing millions of other compounds (4–9). As first presented by this laboratory, nonsupport-bound SCLs have been shown to be usable in virtually any assay system. In an expansion of SCL concepts and diversities, the original peptide SCLs have recently been transformed using a “libraries from libraries” approach (7,10,11a) to yield peptidomimetic and organic libraries having entirely different physical, chemical, and biological properties relative to the peptide SCLs used as starting materials. The screening of a SCL composed of 50 million peptidomimetics (7) has yielded individual active compounds that had no homology to those found in the starting SCLs. We describe here improved methods (10) developed for the transformation of such libraries.
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References
Pinilla C., Appel J.R., Blondelle S.E., Dooley C T., Etchler J., Ostresh J.M., and Houghten R A. (1994) Versatility of positional scanning synthetic combina torial libraries for the identiftcation of individual compounds Drug Dev Res 33, 133–145
Pinilla C., Appel J., Blondelle S E., Dooley C. T., Ddrner B., Etchler J., Ostresh J M., and Houghten R A (1995) A review of the utility of peptide combinatorial libraries Bzopolymers 37, 221–240
Gallop M.A., Barrett R W., Dower W J., Fodor S. P A., and Gordon E M. (1994) Applications of combinatortal technologies to drug discovery 1 Background and peptide combinatorial libraries. J. Med. Chem. 37, 1233–1251
Blondelle S. E., Pérez-Payá E., Dooley C T., Pinilla C., and Houghten R A (1995) Chemical combinatortal Itbrartes, peptidomimetics and peptide diversity. Trends Anal. Chem 14, 83–92
Blondelle S E., Takahashi E., Dinh K. T., and Houghten R A (1995) The antimicrobtal activity of hexapeptides dertved from synthetic combinatortal libraries J. Appl. Bactertol. 78, 39–46
Blondelle S. E., Takahashi E., Weber P. A., and Houghten R A (1994) Identification of antimicrobial peptides using combinatortal libraries made up of unnatural amino acids. Antimicrob. Agents Chemother 38, 2280–2286.
Ostresh J. M., Husar G M., Blondelle S E., Dorner B., Weber P A., and Houghten R. A. (1994) “Ltbrartes from Itbrartes”: chemtcal transformation of combinatortal libraries to extend the range and repertoire of chemtcal diversity Proc. Natl.Acad. Set. USA 91, 11,138–11,142
Houghten R. A., Appel J. R., Blondelle S E., Cuervo J. H., Dooley C. T., and Pinilla C. (1992) The use of synthetic peptide combinatortal libraries for the identification of bioactive peptides Btotechniques 13, 412–421.
Houghten R. A., Pmilla C., Blondelle S E., Appel J. R., Dooley C. T., and Cuervo J H. (1991) Generation and use of synthetic peptide combinatortal libraries for basic research and drug discovery. Nature 354, 84–86.
Dorner B., Ostresh J. M., Husar G M., and Houghten R. A. (1995) Extending the range of molecular diversity through amtde alkylation of peptide libraries, in Peptides 94: Proceedings of the 23rd European Peptide Sympostum (Maia H. L. S, ed), Escom, Letden, pp 463,464.
Cuervo J. H., Weitl F., Ostresh J. M., Hamashm V. T., Hannah A. L., and Houghten R. A. (1995) Polyalkylamme chemical combinatortal libraries, in Peptides 94: Proceedings of the 23rd European Peptide Sympostum, (Maia H. L. S., ed.), Escom, Leaden, pp 465,466.
Nefzi A., Ostresh J. M., Meyer J-P., and Houghten R A. (1997) Solid phase synthesis of heterocycbc compounds from lmear peptides cyclm ureas and thioureas Tetrahedron Lett. 38, 931–934.
Lam K S., Salmon S. E., Hersh E M., Hruby V J., Kazmierskt W M., and Knapp R J. (1991) A new type of synthetic peptide library for identifying ligandbinding activity Nature 354, 82–84
Ostresh J M., Winkle J H., Hamashm V. T., and Houghten R A (1994) Peptide libraries. determination of relative reaction rates of protected amino acids in competitive couplings Btopolymers 34, 1681–1689.
Etchler J and Houghten R A. (1993) Identification of substrate-analog trypsin inhibitors through the screening of synthetic peptide combinatorial libraries Bzochemistry 32, 11,035–11,041
Houghten R. A. (1985) General method for the rapld solld-phase synthesis of large numbers of peptldes speclflclty of antigen-antibody mteraction at the level of individual amino acids Proc. Natl. Acad. Set. USA 82, 5131–5135
Krchnák V., VBgner J., Safk P., and Lebl M (1988) Nonmvaslve contmuous monitoring of solid-phase peptlde synthesis by acid-base indicator Co11 Czech Chem. Comm. 53, 2542–2546
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© 1998 Humana Press Inc., Totowa, NJ
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Ostresh, J.M., Dörner, B., Houghten, R.A. (1998). Peralkylation. In: Cabilly, S. (eds) Combinatorial Peptide Library Protocols. Methods in Molecular Biology™, vol 87. Humana Press. https://doi.org/10.1385/0-89603-392-9:41
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DOI: https://doi.org/10.1385/0-89603-392-9:41
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