Tweezer-like receptor molecules have proven their potential for molecular recognition on several occasions. We decided to make twofold use of this receptor design: firstly to learn whether simple molecular forceps consisting of two peptide chains linked by a spacer are able to selectively bind to small peptides, and secondly to investigate the importance of structural preorganization for the characteristics of the receptors. We prepared two encoded combinatorial libraries based on this design, featuring two combinatorial tripeptide chains held by different scaffolds: the use of chenodeoxycholic acid as spacer provided a rigid scaffold for the forceps, whereas linking the peptide chains by a pentamethylene chain yielded a very flexible forceps structure. Molecules from the cholic acid library recognize and discriminate various enkephalins with micromolar affinities. Molecules from the flexible library show distinct interactions with the enkephalins as well, but the specificity and affinity are clearly diminished. Thus, although the interactions of molecular forceps with peptides are not crucially dependent on structural preorganization, receptors with a rigid design are clearly superior to flexible molecular forceps.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Gallop, M.A., Barrett, R.W., Dower, W.J., Fodor, S.P.A. and Gordon, E.M.,Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries, J. Med. Chem., 37 (1994) 1233–1251.
Gordon, E.M., Barrett, R.W., Dower, W.J., Fodor, S.P.A. and Gallop, M.A.,Applications of combinatorial technologies to drug discovery. 2 Combinatorial organic synthesis, library screening strategies, and future directions, J. Med. Chem., 37 (1994) 1385–1401.
Lebl, M., Krchñák, V., Sepetov, N.F., Seligmann, B., Strop, P., Felder, S. and Lam, K.S.,One-bead-one-structure combinatorial libraries, Biopolymers, 37 (1995) 177–198.
Brenner S. and Lerner, R.A.,Encoded combinatorial chemistry, Proc. Natl. Acad. Sci. USA, 89 (1992) 5381–5383.
Kerr, J.M., Banville, S.C. and Zuckermann, R.N.,Encoded combinatorial peptide libraries containing nonnatural amino acids, J. Am. Chem. Soc., 115 (1993) 2529–2531.
Needles, M.C., Joncs, D.G., Tate, E.H., Heinkel, G.L., Kochersberger, L.M., Dower, W.J., Barrett, R.W. and Gallop, M.A.,Generation and screening of an oligonucleotide-encoded synthetic peptide library Proc. Natl. Acad. Sci. USA, 90 (1993) 10700–10704.
Ohlmeyer, M.H.J., Swanson, R.N., Dillard, L.W., Reader, J.C., Asouline, G., Kobayashi, R., Wigler, M.H. and Still, W.C.,Complex synthetic chemical libraries indexed with molecular tags, Proc. Natl Acad. Sci. USA, 90 (1993) 10922–10926.
Nestler, H.P., Bartlett, P.A. and Still, W.C.,A general method for molecular tagging of encoded combinatorial chemistry libraries, J. Org. Chem., 59 (1994) 4723–4724.
Boyce, R., Li, G., Nestler, H.P., Suenaga, T. and Still, W.C.,Peptidosteroidal receptors for opioid peptides. Sequence-selective binding using a synthetic receptor library, J. Am. Chem. Soc., 116 (1994) 7955–7956.
Gennari, C., Nestler, H.P., Salom, B. and Still, W.C.,Synthetic receptors based on vinylogous sulfonyl peptides, Angew. Chem. Int. Ed. Engl., 34 (1995) 1765–1768.
Moree, W.J., Van Gent, L.C., Van der Marel, G.A. and Liskamp, R.M.J.,Synthesis of peptides containing a sulfinamide or a sulfonamide transition-state isostere, Tetrahedron, 49 (1993) 1133–1150.
Gennari C., Salom, B., Potenza, D. and Williams, A.,Synthesis of sulfonamido-pseudopeptides: New chiral unnatural oligomers, Angew. Chem. Int. Ed. Engl., 33 (1994) 2067–2069.
Borchardt, A. and Still, W.C.,Synthetic receptor binding elucidated with an encoded combinatorial library, J. Am. Chem. Soc., 116 (1994) 373–374.
LaBrenz, S.R. and Kelly, J.W.,Peptidomimetic host that binds a peptide guest affording a β-sheet structure that subsequently selfassembles. A simple receptor mimic, J. Am. Chem. Soc., 117 (1995) 1655–1656.
Wennemers, H., Yoon, S.S. and Still, W.C.,Cyclooligomeric receptors based on trimesic acid and 1,2-diamines. Minimal structure for sequence-selective peptide binding, J. Org. Chem., 60 (1995) 1108–1109.
Stewart, J.M. and Young, J.D., Solid-phase Peptide Synthesis, Pierce Chemical Company, Rockford, IL, U.S.A., 1984.
Furka, Á., Sebestyén, F., Asgedom, M. and Dibô, G.,General method for rapid synthesis of multicomponent peptide mixtures, Int. J. Pept. Protein Res., 37 (1991) 487–493.
Lam, K.S., Salmon, S.E., Hersh, E.M., Hruby, V.J., Kazmierski, W.M. and Knapp, R.J.,A new type of synthetic peptide library for identifying ligand-binding activity, Nature, 354 (1991) 82–86.
Supplementary Material comprising procedures for the preparation and spectroscopical data of compounds5 through8, as well as a listing of the 104 decoded sequences from the assay of the flexible library with5Leu-enkephalin/Disperse Red, can be obtained from the author on request.
About this article
Cite this article
Nestler, H.P. Sequence-selective nonmacrocyclic two-armed receptors for peptides. Mol Divers 2, 35–40 (1996). https://doi.org/10.1007/BF01718698
- Combinatorial libraries
- Molecular recognition
- Receptor libraries