Hydrogen Bond Surrogate Stabilization of β-Hairpins

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2018 Jul 14

PMID 30005156

Citations 18

Authors

Nicholas Sawyer

Paramjit S Arora

Affiliations

Soon will be listed here.

Abstract

Peptide secondary and tertiary structure motifs frequently serve as inspiration for the development of protein-protein interaction (PPI) inhibitors. While a wide variety of strategies have been used to stabilize or imitate α-helices, similar strategies for β-sheet stabilization are more limited. Synthetic scaffolds that stabilize reverse turns and cross-strand interactions have provided important insights into β-sheet stability and folding. However, these templates occupy regions of the β-sheet that might impact the β-sheet's ability to bind at a PPI interface. Here, we present the hydrogen bond surrogate (HBS) approach for stabilization of β-hairpin peptides. The HBS linkage replaces a cross-strand hydrogen bond with a covalent linkage, conferring significant conformational and proteolytic resistance. Importantly, this approach introduces the stabilizing linkage in the buried β-sheet interior, retains all side chains for further functionalization, and allows efficient solid-phase macrocyclization. We anticipate that HBS stabilization of PPI β-sheets will enhance the development of β-sheet PPI inhibitors and expand the repertoire of druggable PPIs.

Citing Articles

Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets.

Colas K, Bindl D, Suga H Chem Rev. 2024; 124(21):12213-12241.

PMID: 39451037 PMC: 11565579. DOI: 10.1021/acs.chemrev.4c00422.

Structural Characterization of Disulfide-Linked p53-Derived Peptide Dimers.

DiGiorno M, Vithanage N, Victorio C, Kreitler D, Outlaw V, Sawyer N Res Sq. 2024; .

PMID: 39070635 PMC: 11275974. DOI: 10.21203/rs.3.rs-4644285/v1.

Structure and biological activity in vitro of Flagellin and its mutants from Escherichia coli Nissle 1917.

Li S, Wen M, Wen G, Yang Y Arch Microbiol. 2024; 206(5):221.

PMID: 38637410 DOI: 10.1007/s00203-024-03907-7.

Stabilized cyclic peptides as modulators of protein-protein interactions: promising strategies and biological evaluation.

Cheng J, Zhou J, Kong L, Wang H, Zhang Y, Wang X RSC Med Chem. 2023; 14(12):2496-2508.

PMID: 38107173 PMC: 10718590. DOI: 10.1039/d3md00487b.

Structure-Based Design and Synthesis of Stapled Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases.

Lamouroux A, Tournier M, Iaculli D, Caufriez A, Rusiecka O, Martin C J Med Chem. 2023; 66(18):13086-13102.

PMID: 37703077 PMC: 10544015. DOI: 10.1021/acs.jmedchem.3c01116.

References

Henchey L, Kushal S, Dubey R, Chapman R, Olenyuk B, Arora P . Inhibition of hypoxia inducible factor 1-transcription coactivator interaction by a hydrogen bond surrogate alpha-helix. J Am Chem Soc. 2010; 132(3):941-3. PMC: 2810346. DOI: 10.1021/ja9082864. View

Chang Y, Graves B, Guerlavais V, Tovar C, Packman K, To K . Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy. Proc Natl Acad Sci U S A. 2013; 110(36):E3445-54. PMC: 3767549. DOI: 10.1073/pnas.1303002110. View

Koide A, Wojcik J, Gilbreth R, Hoey R, Koide S . Teaching an old scaffold new tricks: monobodies constructed using alternative surfaces of the FN3 scaffold. J Mol Biol. 2011; 415(2):393-405. PMC: 3260337. DOI: 10.1016/j.jmb.2011.12.019. View

Holland-Nell K, Meldal M . Maintaining biological activity by using triazoles as disulfide bond mimetics. Angew Chem Int Ed Engl. 2011; 50(22):5204-6. DOI: 10.1002/anie.201005846. View

Wang D, Chen K, Dimartino G, Arora P . Nucleation and stability of hydrogen-bond surrogate-based alpha-helices. Org Biomol Chem. 2007; 4(22):4074-81. PMC: 1807155. DOI: 10.1039/b612891b. View

Richardson J . The anatomy and taxonomy of protein structure. Adv Protein Chem. 1981; 34:167-339. DOI: 10.1016/s0065-3233(08)60520-3. View

Mahon A, Arora P . Design, synthesis and protein-targeting properties of thioether-linked hydrogen bond surrogate helices. Chem Commun (Camb). 2011; 48(10):1416-8. PMC: 3412876. DOI: 10.1039/c1cc14730g. View

Patgiri A, Yadav K, Arora P, Bar-Sagi D . An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol. 2011; 7(9):585-7. PMC: 3312813. DOI: 10.1038/nchembio.612. View

Phillips S, Piersanti G, Bartlett P . Quantifying amino acid conformational preferences and side-chain-side-chain interactions in beta-hairpins. Proc Natl Acad Sci U S A. 2005; 102(39):13737-42. PMC: 1202387. DOI: 10.1073/pnas.0506646102. View

10.

Chapman R, Kulp 3rd J, Patgiri A, Kallenbach N, Bracken C, Arora P . Trapping a folding intermediate of the alpha-helix: stabilization of the pi-helix. Biochemistry. 2008; 47(14):4189-95. PMC: 7183248. DOI: 10.1021/bi800136m. View

11.

Blackwell H, Sadowsky J, Howard R, Sampson J, Chao J, Steinmetz W . Ring-closing metathesis of olefinic peptides: design, synthesis, and structural characterization of macrocyclic helical peptides. J Org Chem. 2001; 66(16):5291-302. DOI: 10.1021/jo015533k. View

12.

Lau Y, Wu Y, de Andrade P, Galloway W, Spring D . A two-component 'double-click' approach to peptide stapling. Nat Protoc. 2015; 10(4):585-94. DOI: 10.1038/nprot.2015.033. View

13.

Cochran A, Tong R, Starovasnik M, Park E, McDowell R, Theaker J . A minimal peptide scaffold for beta-turn display: optimizing a strand position in disulfide-cyclized beta-hairpins. J Am Chem Soc. 2001; 123(4):625-32. DOI: 10.1021/ja003369x. View

14.

Traxlmayr M, Kiefer J, Srinivas R, Lobner E, Tisdale A, Mehta N . Strong Enrichment of Aromatic Residues in Binding Sites from a Charge-neutralized Hyperthermostable Sso7d Scaffold Library. J Biol Chem. 2016; 291(43):22496-22508. PMC: 5077188. DOI: 10.1074/jbc.M116.741314. View

15.

Celentano V, Diana D, De Rosa L, Romanelli A, Fattorusso R, DAndrea L . β-Hairpin stabilization through an interstrand triazole bridge. Chem Commun (Camb). 2011; 48(5):762-4. DOI: 10.1039/c1cc16017f. View

16.

Cooley R, Arp D, Karplus P . Evolutionary origin of a secondary structure: π-helices as cryptic but widespread insertional variations of α-helices that enhance protein functionality. J Mol Biol. 2010; 404(2):232-46. PMC: 2981643. DOI: 10.1016/j.jmb.2010.09.034. View

17.

Kushal S, Lao B, Henchey L, Dubey R, Mesallati H, Traaseth N . Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling. Proc Natl Acad Sci U S A. 2013; 110(39):15602-7. PMC: 3785738. DOI: 10.1073/pnas.1312473110. View

18.

Chapman R, Arora P . Optimized synthesis of hydrogen-bond surrogate helices: surprising effects of microwave heating on the activity of Grubbs catalysts. Org Lett. 2006; 8(25):5825-8. PMC: 1828874. DOI: 10.1021/ol062443z. View

19.

Wang D, Lu M, Arora P . Inhibition of HIV-1 fusion by hydrogen-bond-surrogate-based alpha helices. Angew Chem Int Ed Engl. 2008; 47(10):1879-82. DOI: 10.1002/anie.200704227. View

20.

Moellering R, Cornejo M, Davis T, Del Bianco C, Aster J, Blacklow S . Direct inhibition of the NOTCH transcription factor complex. Nature. 2009; 462(7270):182-8. PMC: 2951323. DOI: 10.1038/nature08543. View