A Rapid Library Screen for Tailoring Beta-peptide Structure and Function

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2005 Oct 20

PMID 16231906

Citations 31

Authors

Joshua A Kritzer

Nathan W Luedtke

Elizabeth A Harker

Alanna Schepartz

Affiliations

Soon will be listed here.

Abstract

Recently we described a beta-decapeptide (beta53-1) that folds into a 14-helix in aqueous solution, binds the oncoprotein hDM2 with submicromolar affinity, and inhibits the interaction of hDM2 with a peptide derived from the activation domain of p53 (p53AD). The solution structure of beta53-1 in CD3OH revealed an unexpected C-terminal unwinding that staggers the side chains comprising the hDM2 recognition epitope to better mimic those of p53AD. The structure-function relationship implied by this distortion suggested that a library of beta53-1 analogues possessing diversity along a nonrecognition face might contain molecules possessing greater affinity for hDM2. Here we describe (1) beta-peptide synthesis protocols that produce high quality one-bead-one-beta-peptide libraries suitable for on-bead screening without purification, (2) a versatile, scalable on-bead screen, and (3) a simple tandem mass spectrometry (MS/MS) decoding method. Using this procedure, we identified beta53-1 analogues with improved structural and functional properties.

Citing Articles

Proteomimetic surface fragments distinguish targets by function.

Tokoli A, Mag B, Bartus E, Weber E, Szakonyi G, Simon M Chem Sci. 2021; 11(38):10390-10398.

PMID: 34094300 PMC: 8162404. DOI: 10.1039/d0sc03525d.

Ultra-large chemical libraries for the discovery of high-affinity peptide binders.

Quartararo A, Gates Z, Somsen B, Hartrampf N, Ye X, Shimada A Nat Commun. 2020; 11(1):3183.

PMID: 32576815 PMC: 7311396. DOI: 10.1038/s41467-020-16920-3.

Developments with bead-based screening for novel drug discovery.

Pei D, Appiah Kubi G Expert Opin Drug Discov. 2019; 14(11):1097-1102.

PMID: 31335229 PMC: 7301614. DOI: 10.1080/17460441.2019.1647164.

In-solution enrichment identifies peptide inhibitors of protein-protein interactions.

Touti F, Gates Z, Bandyopadhyay A, Lautrette G, Pentelute B Nat Chem Biol. 2019; 15(4):410-418.

PMID: 30886434 PMC: 6710073. DOI: 10.1038/s41589-019-0245-2.

Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions.

Roy S, Ghosh P, Ahmed I, Chakraborty M, Naiya G, Ghosh B Biomedicines. 2018; 6(4).

PMID: 30567318 PMC: 6315407. DOI: 10.3390/biomedicines6040118.

References

Kritzer J, Tirado-Rives J, Hart S, Lear J, Jorgensen W, Schepartz A . Relationship between side chain structure and 14-helix stability of beta3-peptides in water. J Am Chem Soc. 2005; 127(1):167-78. PMC: 2873033. DOI: 10.1021/ja0459375. View

Murray J, Farooqi B, Sadowsky J, Scalf M, Freund W, Smith L . Efficient synthesis of a beta-peptide combinatorial library with microwave irradiation. J Am Chem Soc. 2005; 127(38):13271-80. DOI: 10.1021/ja052733v. View

Kussie P, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine A . Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996; 274(5289):948-53. DOI: 10.1126/science.274.5289.948. View

Koradi R, Billeter M, Wuthrich K . MOLMOL: a program for display and analysis of macromolecular structures. J Mol Graph. 1996; 14(1):51-5, 29-32. DOI: 10.1016/0263-7855(96)00009-4. View

Burkoth T, Beausoleil E, Kaur S, Tang D, Cohen F, Zuckermann R . Toward the synthesis of artificial proteins: the discovery of an amphiphilic helical peptoid assembly. Chem Biol. 2002; 9(5):647-54. DOI: 10.1016/s1074-5521(02)00140-0. View

Olivos H, Bachhawat-Sikder K, Kodadek T . Quantum dots as a visual aid for screening bead-bound combinatorial libraries. Chembiochem. 2003; 4(11):1242-5. DOI: 10.1002/cbic.200300712. View

Humet M, Carbonell T, Masip I, Sanchez-Baeza F, Mora P, Canton E . A positional scanning combinatorial library of peptoids as a source of biological active molecules: identification of antimicrobials. J Comb Chem. 2003; 5(5):597-605. DOI: 10.1021/cc020075u. View

Lam K, Lehman A, Song A, Doan N, Enstrom A, Maxwell J . Synthesis and screening of "one-bead one-compound" combinatorial peptide libraries. Methods Enzymol. 2004; 369:298-322. DOI: 10.1016/S0076-6879(03)69017-8. View

Kritzer J, Hodsdon M, Schepartz A . Solution structure of a beta-peptide ligand for hDM2. J Am Chem Soc. 2005; 127(12):4118-9. PMC: 2857645. DOI: 10.1021/ja042933r. View

10.

Kritzer J, Lear J, Hodsdon M, Schepartz A . Helical beta-peptide inhibitors of the p53-hDM2 interaction. J Am Chem Soc. 2004; 126(31):9468-9. DOI: 10.1021/ja031625a. View

11.

Lam K, Lebl M, Krchnak V . The "One-Bead-One-Compound" Combinatorial Library Method. Chem Rev. 1997; 97(2):411-448. DOI: 10.1021/cr9600114. View

12.

Alluri P, Reddy M, Bachhawat-Sikder K, Olivos H, Kodadek T . Isolation of protein ligands from large peptoid libraries. J Am Chem Soc. 2003; 125(46):13995-4004. DOI: 10.1021/ja036417x. View

13.

Figliozzi G, Goldsmith R, Ng S, Banville S, Zuckermann R . Synthesis of N-substituted glycine peptoid libraries. Methods Enzymol. 1996; 267:437-47. DOI: 10.1016/s0076-6879(96)67027-x. View

14.

Murray J, Gellman S . Application of microwave irradiation to the synthesis of 14-helical beta-peptides. Org Lett. 2005; 7(8):1517-20. DOI: 10.1021/ol0501727. View

15.

Murphy J, Uno T, HAMER J, Cohen F, Dwarki V, Zuckermann R . A combinatorial approach to the discovery of efficient cationic peptoid reagents for gene delivery. Proc Natl Acad Sci U S A. 1998; 95(4):1517-22. PMC: 19070. DOI: 10.1073/pnas.95.4.1517. View