Abstract
To speed drug discovery, we developed an approach for identification of individual peptides with a desired biological activity from a library containing millions of peptides. The approach uses sequential orthogonal release of chemically synthesized peptides from insoluble beads, followed by testing in solution. In this system, each bead within a library of beads has one peptide sequence, but peptide molecules are attached to the bead with three types of chemical linkers, including two linkers cleavable at different pH optima. An uncleavable linker keeps some peptide attached to the bead for sequencing positives from the solution assay. Applicability of this discovery technique was documented by identifying ligands for a monoclonal antibody and for the human platelet fibrinogen receptor, glycoprotein IIb/IIIa.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Barker P. L., Bullens S., Bunting S., Burdick D. J., Chan K. S., Deisher T., Eigenbrot C., Gadek T. R., Gantzos R., Lipari M. T. Cyclic RGD peptide analogues as antiplatelet antithrombotics. J Med Chem. 1992 May 29;35(11):2040–2048. doi: 10.1021/jm00089a014. [DOI] [PubMed] [Google Scholar]
- Brenner S., Lerner R. A. Encoded combinatorial chemistry. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5381–5383. doi: 10.1073/pnas.89.12.5381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cwirla S. E., Peters E. A., Barrett R. W., Dower W. J. Peptides on phage: a vast library of peptides for identifying ligands. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6378–6382. doi: 10.1073/pnas.87.16.6378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Devlin J. J., Panganiban L. C., Devlin P. E. Random peptide libraries: a source of specific protein binding molecules. Science. 1990 Jul 27;249(4967):404–406. doi: 10.1126/science.2143033. [DOI] [PubMed] [Google Scholar]
- Fodor S. P., Read J. L., Pirrung M. C., Stryer L., Lu A. T., Solas D. Light-directed, spatially addressable parallel chemical synthesis. Science. 1991 Feb 15;251(4995):767–773. doi: 10.1126/science.1990438. [DOI] [PubMed] [Google Scholar]
- Furka A., Sebestyén F., Asgedom M., Dibó G. General method for rapid synthesis of multicomponent peptide mixtures. Int J Pept Protein Res. 1991 Jun;37(6):487–493. doi: 10.1111/j.1399-3011.1991.tb00765.x. [DOI] [PubMed] [Google Scholar]
- Geysen H. M., Rodda S. J., Mason T. J., Tribbick G., Schoofs P. G. Strategies for epitope analysis using peptide synthesis. J Immunol Methods. 1987 Sep 24;102(2):259–274. doi: 10.1016/0022-1759(87)90085-8. [DOI] [PubMed] [Google Scholar]
- Houghten R. A., Pinilla C., Blondelle S. E., Appel J. R., Dooley C. T., Cuervo J. H. Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature. 1991 Nov 7;354(6348):84–86. doi: 10.1038/354084a0. [DOI] [PubMed] [Google Scholar]
- Kieffer N., Phillips D. R. Platelet membrane glycoproteins: functions in cellular interactions. Annu Rev Cell Biol. 1990;6:329–357. doi: 10.1146/annurev.cb.06.110190.001553. [DOI] [PubMed] [Google Scholar]
- Lam K. S., Salmon S. E., Hersh E. M., Hruby V. J., Kazmierski W. M., Knapp R. J. A new type of synthetic peptide library for identifying ligand-binding activity. Nature. 1991 Nov 7;354(6348):82–84. doi: 10.1038/354082a0. [DOI] [PubMed] [Google Scholar]
- Lebl M., Pátek M., Kocis P., Krchnák V., Hruby V. J., Salmon S. E., Lam K. S. Multiple release of equimolar amounts of peptides from a polymeric carrier using orthogonal linkage-cleavage chemistry. Int J Pept Protein Res. 1993 Feb;41(2):201–203. doi: 10.1111/j.1399-3011.1993.tb00132.x. [DOI] [PubMed] [Google Scholar]
- Maeji N. J., Bray A. M., Geysen H. M. Multi-pin peptide synthesis strategy for T cell determinant analysis. J Immunol Methods. 1990 Nov 6;134(1):23–33. doi: 10.1016/0022-1759(90)90108-8. [DOI] [PubMed] [Google Scholar]
- Nikolaiev V., Stierandová A., Krchnák V., Seligmann B., Lam K. S., Salmon S. E., Lebl M. Peptide-encoding for structure determination of nonsequenceable polymers within libraries synthesized and tested on solid-phase supports. Pept Res. 1993 May-Jun;6(3):161–170. [PubMed] [Google Scholar]
- Scott J. K., Smith G. P. Searching for peptide ligands with an epitope library. Science. 1990 Jul 27;249(4967):386–390. doi: 10.1126/science.1696028. [DOI] [PubMed] [Google Scholar]
- Simon R. J., Kania R. S., Zuckermann R. N., Huebner V. D., Jewell D. A., Banville S., Ng S., Wang L., Rosenberg S., Marlowe C. K. Peptoids: a modular approach to drug discovery. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9367–9371. doi: 10.1073/pnas.89.20.9367. [DOI] [PMC free article] [PubMed] [Google Scholar]