β-Hairpin Peptidomimetics: Design, Structures and Biological Activities

Robinson, John A.

doi:10.1021/ar700259k

Cited by 321Chemical Synthesis and AnalysisProtein Structure and DynamicsBiochemical and Structural Characterization

β-Hairpin Peptidomimetics: Design, Structures and Biological Activities

Robinson, John A.·2008·Accounts of Chemical Research

DOI 10.1021/ar700259k

Open this paper in CoChat — free account

Abstract

The folded 3D structures of peptides and proteins provide excellent starting points for the design of synthetic molecules that mimic key epitopes (or surface patches) involved in protein-protein and protein-nucleic acid interactions. Protein epitope mimetics (PEMs) may recapitulate not only the structural and conformational properties of the target epitope but also their biological activities. By transferring the epitope from a recombinant to a synthetic scaffold that can be produced by parallel combinatorial methods, it is possible to optimize properties through iterative cycles of library synthesis and screening, and even to evolve new biological activities. One very interesting scaffold is found in beta-hairpin motifs, which are used by many proteins to mediate molecular recognition events. This motif is readily amenable to PEM design, for example, by transplanting hairpin loop sequences from folded proteins onto hairpin-stabilizing templates, such as the dipeptide D-Pro-L-Pro. In addition, beta-hairpin peptidomimetics can also be exploited to mimic other types of epitopes, such as those based on alpha-helical secondary structures. The size and shape of beta-hairpin PEMs appear well suited for the design of inhibitors of both protein-protein and protein-nucleic acid interactions, endeavors that have so far proven difficult using small "drug-like" molecules. In recent work, it was shown that beta-hairpin PEMs can be designed that mimic the canonical conformations of antibody hypervariable loops, suggesting that novel small-molecule antibody mimics may be feasible. Using naturally occurring peptides as starting points, beta-hairpin mimetics have been discovered that possess antimicrobial activity, while others are potent inhibitors of the chemokine receptor CXCR4. Beta-hairpin PEMs have also been designed and optimized that mimic an alpha-helical epitope in p53 and so block its interaction with HDM2. A crystal structure of one HDM2-mimetic complex revealed how the surface of the protein had adapted to the shape of the hairpin, thereby enhancing inhibitor affinity. Small folded RNA motifs also make interesting targets for inhibitor design. For example, beta-hairpin mimetics have been designed and optimized that bind with high affinity and good selectivity to the TAR and RRE RNA motifs from HIV-1. Solution structures of the mimetics both free and bound to the RNA target provided some surprises, as well as an improved understanding of the mechanisms of binding. These mimetics represent still a relatively new family of RNA-binding molecules, but clearly one with potential for development into novel antiviral agents.

Integrity signals

Registry

Crossref · 10.1021/ar700259k

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?
Brogden, K. A. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1098 · Cited by 5,829 · see citing works
Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies
Hancock, R. E. W., & Sahl, H. (2006) · Nature Biotechnology · doi:10.1038/nbt1267 · Cited by 4,233 · see citing works
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206 · see citing works
A Hot Spot of Binding Energy in a Hormone-Receptor Interface
Clackson, T., & Wells, J. A. (1995) · Science · doi:10.1126/science.7529940 · Cited by 1,987 · see citing works
Reaching for high-hanging fruit in drug discovery at protein–protein interfaces
Wells, J. A., & McClendon, C. L. (2007) · Nature · doi:10.1038/nature06526 · Cited by 1,963 · see citing works
Conformations of immunoglobulin hypervariable regions
Chothia, C., Lesk, A. M., Tramontano, A. L., Levitt, M., Smith‐Gill, S. J., Air, G. M., Sheriff, S., PADLAN, E. A., Davies, D. R., Tulip, W. R., et al. (1989) · Nature · doi:10.1038/342877a0 · Cited by 1,185 · see citing works
Unraveling hot spots in binding interfaces: progress and challenges
DeLano, W. L. (2002) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(02)00283-x · Cited by 767 · see citing works
Tryptophan zippers: Stable, monomeric β-hairpins
Cochran, A. G., Skelton, N. J., & Starovasnik, M. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091100898 · Cited by 741 · see citing works
Convergent Solutions to Binding at a Protein-Protein Interface
DeLano, W. L., Ultsch, M. H., de, A. M., Vos, & Wells, J. A. (2000) · Science · doi:10.1126/science.287.5456.1279 · Cited by 673 · see citing works
Beyond Watson and Crick: DNA Methylation and Molecular Enzymology of DNA Methyltransferases
Jeltsch, A. (2002) · ChemBioChem · doi:10.1002/1439-7633(20020402)3:4 · Cited by 614 · see citing works
α Helix-RNA Major Groove Recognition in an HIV-1 Rev Peptide-RRE RNA Complex
Battiste, J. L., Mao, H., Rao, N. S., Tan, R., Muhandiram, D. R., Kay, L. E., Frankel, A. D., & Williamson, J. R. (1996) · Science · doi:10.1126/science.273.5281.1547 · Cited by 596 · see citing works
Energetics of protein-protein interactions: Analysis ofthe Barnase-Barstar interface by single mutations and double mutant cycles
Schreiber, G., & Fersht, A. R. (1995) · Journal of Molecular Biology · doi:10.1016/s0022-2836(95)80064-6 · Cited by 566 · see citing works
β-Hairpin families in globular proteins
Sibanda, B. L., & Thornton, J. M. (1985) · Nature · doi:10.1038/316170a0 · Cited by 540 · see citing works
Conformation of β-hairpins in protein structures
Sibanda, B. L., Blundell, T. L., & Thornton, J. M. (1989) · Journal of Molecular Biology · doi:10.1016/0022-2836(89)90583-4 · Cited by 475 · see citing works
The bicyclam AMD3100 story
Clercq, E. D. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1134 · Cited by 460 · see citing works
High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds
Luckett, S., Garcia, R. S., Barker, J. J., et al. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.2891 · Cited by 396 · see citing works
Solution Structure of a Bovine Immunodeficiency Virus Tat-TAR Peptide-RNA Complex
Puglisi, J. D., Chen, L., Blanchard, S. C., & Frankel, A. D. (1995) · Science · doi:10.1126/science.270.5239.1200 · Cited by 339 · see citing works
Discovery of Potent Antagonists of the Interaction between Human Double Minute 2 and Tumor Suppressor p53
Garcı́a-Echeverrı́a, C., Chêne, P., Blommers, M. J. J., & Furet, P. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm990966p · Cited by 246 · see citing works
The N-terminal Domain of p53 is Natively Unfolded
Dawson, R. J. P., Müller, L., Dehner, A., Klein, C., Kessler, H., & Büchner, J. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.08.008 · Cited by 228 · see citing works
The molecular architecture of protein–protein binding sites
Reichmann, D., Rahat, O., Cohen, M., Neuvirth, H., & Schreiber, G. (2007) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2007.01.004 · Cited by 198 · see citing works
Exploring Protein–Protein Interactions with Phage Display
Sidhu, S. S., Fairbrother, W. J., & Deshayes, K. (2003) · ChemBioChem · doi:10.1002/cbic.200390008 · Cited by 189 · see citing works
Targeting protein–protein interactions: Lessons from p53/MDM2
Murray, J. K., & Gellman, S. H. (2007) · Biopolymers · doi:10.1002/bip.20741 · Cited by 186 · see citing works
Using a β‐Hairpin To Mimic an α‐Helix: Cyclic Peptidomimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction
Fasan, R., Dias, R. L. A., Moehle, K., Zerbe, O., Vrijbloed, J. W., Obrecht, D., & Robinson, J. A. (2004) · Angewandte Chemie International Edition · doi:10.1002/anie.200353242 · Cited by 183 · see citing works
Self-citation
Beta-hairpins in proteins revisited: lessons for de novo design
Gunasekaran, K., Ramakrishnan, C., & Balaram, P. (1997) · Protein Engineering Design and Selection · doi:10.1093/protein/10.10.1131 · Cited by 178 · see citing works
The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target
Burger, J. A., & Bürkle, A. (2007) · British Journal of Haematology · doi:10.1111/j.1365-2141.2007.06590.x · Cited by 161 · see citing works
A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity
Ichiyama, K., Yokoyama-Kumakura, S., Tanaka, Y., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0630420100 · Cited by 155 · see citing works
In Vivo Photocrosslinking with Unnatural Amino Acid Mutagenesis
Chin, J. W., & Schultz, P. G. (2002) · ChemBioChem · doi:10.1002/1439-7633(20021104)3:11 · Cited by 149 · see citing works
Structure of Free MDM2 N-terminal Domain Reveals Conformational Adjustments that Accompany p53-binding
Uhrı́nová, S., Uhrı́n, D., Powers, H., Watt, K., Zheleva, D. I., Fischer, P. M., McInnes, C., & Barlow, P. N. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.05.010 · Cited by 141 · see citing works
Pro-D-NMe-Amino Acid and D-Pro-NMe-Amino Acid: Simple, Efficient Reverse-Turn Constraints
Chalmers, D. K., & Marshall, G. R. (1995) · Journal of the American Chemical Society · doi:10.1021/ja00127a004 · Cited by 137 · see citing works
Structure–Activity Studies in a Family of β‐Hairpin Protein Epitope Mimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction
Fasan, R., Dias, R. L. A., Moehle, K., Zerbe, O., Obrecht, D., Mittl, P. R. E., Grütter, M. G., & Robinson, J. A. (2006) · ChemBioChem · doi:10.1002/cbic.200500452 · Cited by 129 · see citing works
Self-citation
p53—A Natural Cancer Killer: Structural Insights and Therapeutic Concepts
Römer, L., Klein, C., Dehner, A., Kessler, H., & Büchner, J. (2006) · Angewandte Chemie International Edition · doi:10.1002/anie.200600611 · Cited by 115 · see citing works
Structural Mimicry of Canonical Conformations in Antibody Hypervariable Loops Using Cyclic Peptides Containing a Heterochiral Diproline Template
Favre, M., Moehle, K., Jiang, L., Pfeiffer, B., & Robinson, J. A. (1999) · Journal of the American Chemical Society · doi:10.1021/ja984016p · Cited by 113 · see citing works
Self-citation
Structural Mimicry of Retroviral Tat Proteins by Constrained β-Hairpin Peptidomimetics: Ligands with High Affinity and Selectivity for Viral TAR RNA Regulatory Elements
Athanassiou, Z., Dias, R. L. A., Moehle, K., Dobson, N., Varani, G., & Robinson, J. A. (2004) · Journal of the American Chemical Society · doi:10.1021/ja0497680 · Cited by 96 · see citing works
Self-citation
Protein Ligand Design: From Phage Display to Synthetic Protein Epitope Mimetics in Human Antibody Fc-Binding Peptidomimetics
Dias, R. L. A., Fasan, R., Moehle, K., Renard, A., Obrecht, D., & Robinson, J. A. (2006) · Journal of the American Chemical Society · doi:10.1021/ja057513w · Cited by 93 · see citing works
Self-citation
Conformational analysis of cyclic hexapeptides containing the D-Pro-L-Pro sequence to fix .beta.-turn positions
Bean, J. W., Kopple, K. D., & Peishoff, C. E. (1992) · Journal of the American Chemical Society · doi:10.1021/ja00039a050 · Cited by 89 · see citing works
Discovery of novel, highly potent and selective β-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles
DeMarco, S. J., Henze, H., Lederer, A., et al. (2006) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2006.09.003 · Cited by 88 · see citing works
Properties and structure–activity studies of cyclic β-hairpin peptidomimetics based on the cationic antimicrobial peptide protegrin I
Robinson, J. A., Shankaramma, S. C., Jetter, P., Kienzl, U., Schwendener, R. A., Vrijbloed, J. W., & Obrecht, D. (2005) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2005.01.009 · Cited by 80 · see citing works
Self-citation
Structure-Guided Peptidomimetic Design Leads to Nanomolar β-Hairpin Inhibitors of the Tat−TAR Interaction of Bovine Immunodeficiency Virus,
Athanassiou, Z., Patora‐Komisarska, K., Dias, R. L. A., Moehle, K., Robinson, J. A., & Varani, G. (2006) · Biochemistry · doi:10.1021/bi0619371 · Cited by 75 · see citing works
Self-citation
Chemical and functional diversity of small molecule ligands for RNA
Hermann, T. (2003) · Biopolymers · doi:10.1002/bip.10410 · Cited by 74 · see citing works
New Insights into Aminoglycoside Antibiotics and Derivatives
da Silva, J. G., & Carvalho, I. (2007) · Current Medicinal Chemistry · doi:10.2174/092986707780362817 · Cited by 64 · see citing works
X-Ray crystal structure of pivaloyl- D -Pro- L -Pro- L -Ala-N-methylamide; observation of a consecutive β-turn conformation
Nair, C. M., Vijayan, M., Venkatachalapathi, Y. V., et al. (1979) · Journal of the Chemical Society Chemical Communications · doi:10.1039/c39790001183 · Cited by 63 · see citing works
TAR RNA Recognition by a Cyclic Peptidomimetic of Tat Protein,
Leeper, T. C., Athanassiou, Z., Dias, R. L. A., et al. (2005) · Biochemistry · doi:10.1021/bi0510532 · Cited by 62 · see citing works
QSAR analysis of antimicrobial and haemolytic effects of cyclic cationic antimicrobial peptides derived from protegrin-1
Frecer, V. (2006) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2006.05.005 · Cited by 59 · see citing works
Design of β‐Hairpin Peptidomimetics That Inhibit Binding of α‐Helical HIV‐1 Rev Protein to the Rev Response Element RNA
Moehle, K., Athanassiou, Z., Patora, K., et al. (2007) · Angewandte Chemie International Edition · doi:10.1002/anie.200702801 · Cited by 50 · see citing works
Stabilization of aβ-Hairpin Conformation in a Cyclic Peptide Using the Templating Effect of a Heterochiral Diproline Unit
Späth, J., Stuart, F., Jiang, L., & Robinson, J. A. (1998) · Helvetica Chimica Acta · doi:10.1002/(sici)1522-2675(19980909)81:9 · Cited by 41 · see citing works
Self-citation
A family of macrocyclic antibiotics with a mixed peptide–peptoid ß-hairpin backbone conformation
Shankaramma, S. C., Moehle, K., James, S. P., Vrijbloed, J. W., Obrecht, D., & Robinson, J. A. (2003) · Chemical Communications · doi:10.1039/b304310j · Cited by 37 · see citing works
Self-citation
Mdm2: p53's Lifesaver?
Shmueli, A., & Oren, M. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.03.006 · Cited by 36 · see citing works
Development of Low Molecular Weight CXCR4 Antagonists by Exploratory Structural Tuning of Cyclic Tetra- and Pentapeptide-Scaffolds Towards the Treatment of HIV Infection, Cancer Metastasis and Rheumatoid Arthritis
Tamamura, H., Tsutsumi, H., Masuno, H., et al. (2006) · Current Medicinal Chemistry · doi:10.2174/092986707779313499 · Cited by 36 · see citing works
Biaryl amino acid templates in place of d-Pro-l-Pro in cyclic ß-hairpin cationic antimicrobial peptidomimetics
Srinivas, N., Moehle, K., Abou‐Hadeed, K., et al. (2007) · Organic & Biomolecular Chemistry · doi:10.1039/b706370a · Cited by 19 · see citing works
On the Influence of the Carbohydrate Moiety on Chromophore Formation during Food-RelatedMaillard Reactions of Pentoses, Hexoses, and Disaccharides
Frank, O., & Hofmann, T. F. (2000) · Helvetica Chimica Acta · doi:10.1002/1522-2675(20001220)83:12 · Cited by 11 · see citing works
Horizons in Chemical Immunology – Approaches to Synthetic Vaccine Design
Robinson, J. A. (2007) · CHIMIA International Journal for Chemistry · doi:10.2533/chimia.2007.84 · Cited by 8 · see citing works
Self-citation

Flagged first, then by citations

Sorted by citations

Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497 · see citing works
Systematic Targeting of Protein–Protein Interactions
Modell, A. E., Blosser, S. L., & Arora, P. S. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.05.008 · Cited by 184 · see citing works
Constrained Peptides with Target‐Adapted Cross‐Links as Inhibitors of a Pathogenic Protein–Protein Interaction
Glas, A., Bier, D., Hahne, G., Rademacher, C., Ottmann, C., & Grossmann, T. N. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201310082 · Cited by 145 · see citing works
A Left‐Handed Solution to Peptide Inhibition of the p53–MDM2 Interaction
Liu, M., Pazgier, M., Li, C., Yuan, W., Li, C., & Lu, W. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.201000329 · Cited by 115 · see citing works
A protein tertiary structure mimetic modulator of the Hippo signalling pathway
Adihou, H., Gopalakrishnan, R., Förster, T., Guéret, S. M., Gasper, R., Geschwindner, S., Carrillo García, C., Karatas, H., Pobbati, A. V., Vazquez‐Chantada, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19224-8 · Cited by 58 · see citing works

Synthetic Approaches towards Peptidomimetic Design
Trabocchi, A., & Guarna, A. (2014) · doi:10.1002/9781118683033.ch2 · Cited by 1 · see citing works
Rational design of enzyme activity and enantioselectivity
Song, Z., Zhang, Q., Wu, W., Pu, Z., & Yu, H. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1129149 · Cited by 171 · see citing works
Protein Structure Design and Engineering
Berry, S. M., & Lu, Y. (2011) · Encyclopedia of Life Sciences · doi:10.1002/9780470015902.a0002983.pub2 · Cited by 2 · see citing works
Rational Design of Protein Cages for Alternative Enzymatic Functions
Marshall, N., Miner, K. D., Wilson, T. D., & Lu, Y. (2013) · Wiley eBooks · doi:10.1002/9781118571811.ch5 · Cited by 6 · see citing works
Rational-Design Engineering to Improve Enzyme Thermostability
Pongsupasa, V., Anuwan, P., Maenpuen, S., et al. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1826-4_9 · Cited by 35 · see citing works

Authors: Robinson, J. A.
Affiliations: University of Zurich (CH)
Corresponding author: Robinson, John A.
ORCID: Robinson, John A.
Venue: Accounts of Chemical Research
Publisher: American Chemical Society (ACS)
Published: 2008-04-16
Volume: 41
Issue: 10
Pages: 1278-1288
ISSN: 0001-4842 (ISSN-L)
1520-4898
DOI: 10.1021/ar700259k
OpenAlex: W1999253307
Cited by: 321
References: 51
Citations by year: 2026: 3 · 2025: 13 · 2024: 10 · 2023: 12 · 2022: 10 · 2021: 17 · 2020: 16 · 2019: 14 · 2018: 16 · 2017: 16 · 2016: 28 · 2015: 24 · 2014: 25 · 2013: 31 · 2012: 19
FWCI: 9.45
Type: journal article
Language: en
Open access: closed
Locations: Accounts of Chemical Research (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
Keywords: protein-protein interaction, protein-nucleic acid interactions, antibody mimics, CXCR4 antagonist, p53-MDM2 interaction, antimicrobial peptides, combinatorial library design
MeSH terms: Anti-Infective Agents, Antibodies, Antiviral Agents, Models, Molecular, Peptides, Protease Inhibitors, Protein Binding, Proteins, RNA, Drug Design, Protein Structure, Secondary, Receptors, Cytokine, Crystallography, X-Ray, Biomimetic Materials

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

β-Hairpin Peptidomimetics: Design, Structures and Biological Activities

Abstract

Integrity signals

Claims the paper makes

Cites

Cited by

Related

Record

About these checks