Download PDF
CC BY 4.0 · Synlett
DOI: 10.1055/a-2308-1795
account

From Protein Structures to Functional Biomimetics

Canan Durukan
a   Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
b   Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
,
Tom N. Grossmann  ∗
a   Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
b   Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
› Author AffiliationsWe are grateful for support by the Fonds der Chemischen Industrie (661413), the German Research Foundation (DFG, Emmy Noether program GR3592/2-1), the European Research Council (ERC starting grant 678623; ERC proof-of-concept 839088, 101067731, 101112973), the Dutch Research Council (NWO 00838037, 01291832), and the Dutch Cancer Society (KWF 15036). This work was also supported by AstraZeneca, Bayer Crop Science, Bayer HealthCare, Boehringer Ingelheim, Merck KGaA, and the Max Planck Society.
› Further Information
   Permissions and Reprints All articles of this category


Abstract

The development of complex molecular scaffolds with defined folding properties represents a central challenge in chemical research. Proteins are natural scaffolds defined by a hierarchy of structural complexity and have evolved to manifest unique functional characteristics; for example, molecular recognition capabilities that facilitate the binding of target molecules with high affinity and selectivity. Utilizing these features, proteins have been used as a starting point for the design of synthetic foldamers and enhanced biocatalysts, as well as bioactive reagents in drug discovery. In this account, we describe the strategies used in our group to stabilize protein folds, ranging from the constraint of bioactive peptide conformations to chemical protein engineering. We discuss the evolution of peptides into peptidomimetics to inhibit protein–protein and protein–nucleic acid interactions, and the selective chemical modification of proteins to enhance their properties for biotechnological applications. The reported peptide- and proteomimetic structures cover a broad range of molecular sizes and they highlight the importance of structure stabilization for the design of functional biomimetics.

1 Introduction

2 Constraining the Conformation of Peptides

3 Peptide-Based Covalent Protein Modifiers

4 Chemical Protein Engineering

5 Conclusions

Key words

INCYPRO - peptidomimetics - protein engineering - protein–protein interactions - proteomimetics - structure-based design


Publication History

Received: 02 April 2024

Accepted after revision: 16 April 2024

Accepted Manuscript online:
17 April 2024

Article published online:
08 May 2024

© 2024. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

    • 1a Marsh JA, Teichmann SA. PLoS Biol. 2014; 12: e1001870
      CrossrefPubMed
    • 1b Dobson CM, Šali A, Karplus M. Angew. Chem. Int. Ed. 1998; 37: 868
      CrossrefPubMed
    • 2a Gellman SH. Acc. Chem. Res. 1998; 31: 173
      Crossref
    • 2b Horne WS, Grossmann TN. Nat. Chem. 2020; 12: 331
      CrossrefPubMed
    • 3a Milroy L.-G, Grossmann TN, Hennig S, Brunsveld L, Ottmann C. Chem. Rev. 2014; 114: 4695
      CrossrefPubMed
    • 3b Pelay-Gimeno M, Glas A, Koch O, Grossmann TN. Angew. Chem. Int. Ed. 2015; 54: 8896
      CrossrefPubMed
    • 3c Valeur E, Guéret SM, Adihou H, Gopalakrishnan R, Lemurell M, Waldmann H, Grossmann TN, Plowright AT. Angew. Chem. Int. Ed. 2017; 56: 10294
      CrossrefPubMed
  • 4 Lenci E, Trabocchi A. Chem. Soc. Rev. 2020; 49: 3262
    CrossrefPubMed
  • 5 Algar S, Martín-Martínez M, González-Muñiz R. Eur. J. Med. Chem. 2021; 211: 113015
    CrossrefPubMed
  • 6 Maculins T, Garcia-Pardo J, Skenderovic A, Gebel J, Putyrski M, Vorobyov A, Busse P, Varga G, Kuzikov M, Zaliani A. Cell Chem. Biol. 2020; 27: 1441
    CrossrefPubMed
    • 7a Glas A, Bier D, Hahne G, Rademacher C, Ottmann C, Grossmann TN. Angew. Chem. Int. Ed. 2014; 53: 2489
      CrossrefPubMed
    • 7b Wendt M, Bellavita R, Gerber A, Efrém NL, van Ramshorst T, Pearce NM, Davey PR, Everard I, Vazquez-Chantada M, Chiarparin E. Angew. Chem. Int. Ed. 2021; 60: 13937
      CrossrefPubMed
    • 8a Paulussen FM, Schouten GK, Moertl C, Verheul J, Hoekstra I, Koningstein GM, Hutchins GH, Alkir A, Luirink RA, Geerke DP. J. Am. Chem. Soc. 2022; 144: 15303
      CrossrefPubMed
    • 8b Adihou H, Gopalakrishnan R, Förster T, Guéret SM, Gasper R, Geschwindner S, Carrillo García C, Karatas H, Pobbati AV, Vazquez-Chantada M. Nat. Commun. 2020; 11: 5425
      CrossrefPubMed
  • 9 Pelay-Gimeno M, Bange T, Hennig S, Grossmann TN. Angew. Chem. Int. Ed. 2018; 57: 11164
    CrossrefPubMed
  • 10 Hutchins GH, Kiehstaller S, Poc P, Lewis AH, Oh J, Sadighi R, Pearce NM, Ibrahim M, Drienovská I, Rijs AM. Chem 2023; 10: 615
    • 11a Cromm PM, Spiegel J, Grossmann TN. ACS Chem. Biol. 2015; 10: 1362
      CrossrefPubMed
    • 11b Chu Q, Moellering RE, Hilinski GJ, Kim Y.-W, Grossmann TN, Yeh JT.-H, Verdine GL. MedChemComm 2015; 6: 111
      Crossref
    • 11c Kim Y.-W, Grossmann TN, Verdine GL. Nat. Protoc. 2011; 6: 761
      CrossrefPubMed
    • 11d Schafmeister CE, Po J, Verdine GL. J. Am. Chem. Soc. 2000; 122: 5891
      Crossref
  • 12 Glas A, Grossmann TN. Synlett 2015; 26: 1
    Article in Thieme Connect
  • 13 Glas A, Wamhoff EC, Krüger DM, Rademacher C, Grossmann TN. Chem. Eur. J. 2017; 23: 16157
    CrossrefPubMed
  • 14 Krüger DM, Glas A, Bier D, Pospiech N, Wallraven K, Dietrich L, Ottmann C, Koch O, Hennig S, Grossmann TN. J. Med. Chem. 2017; 60: 8982
    CrossrefPubMed
  • 15 Wallraven K, Holmelin FL, Glas A, Hennig S, Frolov AI, Grossmann TN. Chem. Sci. 2020; 11: 2269
    CrossrefPubMed
  • 16 Cromm PM, Wallraven K, Glas A, Bier D, Fürstner A, Ottmann C, Grossmann TN. ChemBioChem 2016; 17: 1915
    CrossrefPubMed
  • 17 Blackwell HE, Grubbs RH. Angew. Chem. Int. Ed. 1998; 37: 3281
    CrossrefPubMed
  • 18 Toniolo C, Crisma M, Formaggio F, Valle C, Cavicchioni G, Precigoux G, Aubry A, Kamphuis J. Biopolymers 1993; 33: 1061
    CrossrefPubMed
    • 19a Cromm PM, Spiegel J, Grossmann TN, Waldmann H. Angew. Chem. Int. Ed. 2015; 54: 13516
      CrossrefPubMed
    • 19b Spiegel J, Cromm PM, Zimmermann G, Grossmann TN, Waldmann H. Nat. Chem. Biol. 2014; 10: 613
      CrossrefPubMed
  • 20 Spiegel J, Cromm PM, Itzen A, Goody RS, Grossmann TN, Waldmann H. Angew. Chem. Int. Ed. 2014; 53: 2498
    CrossrefPubMed
  • 21 Cromm PM, Spiegel J, Küchler P, Dietrich L, Kriegesmann J, Wendt M, Goody RS, Waldmann H, Grossmann TN. ACS Chem. Biol. 2016; 11: 2375
    CrossrefPubMed
  • 22 Cromm PM, Schaubach S, Spiegel J, Fürstner A, Grossmann TN, Waldmann H. Nat. Commun. 2016; 7: 11300
    CrossrefPubMed
  • 23 Jeganathan S, Wendt M, Kiehstaller S, Brancaccio D, Kuepper A, Pospiech N, Carotenuto A, Novellino E, Hennig S, Grossmann TN. Angew. Chem. Int. Ed. 2019; 58: 17351 ; Angew. Chem. 2019, 131, 17512
    CrossrefPubMed
  • 24 Nardini M, Gnesutta N, Donati G, Gatta R, Forni C, Fossati A, Vonrhein C, Moras D, Romier C, Bolognesi M. Cell 2013; 152: 132
    CrossrefPubMed
  • 25 Durukan C, Arbore F, Klintrot R, Bigiotti C, Ilie IM, Vreede J, Grossmann TN, Hennig S. ChemBioChem 2024; e202400020
    CrossrefPubMed
  • 26 Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X, He F, Wang Y, Zhang Z, Wang W. Cancer Cell 2014; 25: 166
    CrossrefPubMed
    • 27a Koelman EM, Yeste-Vázquez A, Grossmann TN. Bioorg. Med. Chem. 2022; 70: 116920
      CrossrefPubMed
    • 27b Hahne G, Grossmann TN. Bioorg. Med. Chem. 2013; 21: 4020
      CrossrefPubMed
  • 28 McCoy MA, Spicer D, Wells N, Hoogewijs K, Fiedler M, Baud MG. J. Med. Chem. 2022; 65: 7246
    CrossrefPubMed
  • 29 Grossmann TN, Yeh JT.-H, Bowman BR, Chu Q, Moellering RE, Verdine GL. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 17942
    CrossrefPubMed
  • 30 Held A, Glas A, Dietrich L, Bollmann M, Brandstädter K, Grossmann T, Lohmann C, Pap T, Bertrand J. Osteoarthritis and Cartilage 2018; 26: 818
    CrossrefPubMed
  • 31 Dietrich L, Rathmer B, Ewan K, Bange T, Heinrichs S, Dale TC, Schade D, Grossmann TN. Cell Chem. Biol. 2017; 24: 958
    CrossrefPubMed
  • 32 Huber AH, Weis WI. Cell 2001; 105: 391
    CrossrefPubMed
    • 33a Ellenbroek B, Kahler JP, Evers SR, Pomplun SJ. Angew. Chem. Int. Ed. 2024; e202401704
      PubMed
    • 33b Pal S, tHart P. Front. Mol. Biosci. 2022; 9: 883060
      CrossrefPubMed
  • 34 Chen HY, Yang J, Lin C, Yuan YA. EMBO Rep. 2008; 9: 754
    CrossrefPubMed
  • 35 Kuepper A, McLoughlin NM, Neubacher S, Yeste-Vázquez A, Collado Camps E, Nithin C, Mukherjee S, Bethge L, Bujnicki JM, Brock R. Nucleic Acids Res. 2021; 49: 12622
    CrossrefPubMed
  • 36 McLoughlin NM, Albers MA, Collado Camps E, Paulus J, Ran YA, Neubacher S, Hennig S, Brock R, Grossmann TN. Angew. Chem. Int. Ed. 2023; 62: e202308028
    CrossrefPubMed
  • 37 McLoughlin NM, Kuepper A, Neubacher S, Grossmann TN. Chem. Eur. J. 2021; 27: 10477
    CrossrefPubMed
  • 38 Shiraiwa K, Cheng R, Nonaka H, Tamura T, Hamachi I. Cell Chem. Biol. 2020; 27: 970
    CrossrefPubMed
    • 39a Brauckhoff N, Fang L, Haim A, Grossmann TN. Chem. Commun. 2023; 59: 5241
      CrossrefPubMed
    • 39b Brauckhoff N, Hahne G, Yeh JT. H, Grossmann TN. Angew. Chem. Int. Ed. 2014; 53: 4337
      CrossrefPubMed
    • 39c Lee CU, Grossmann TN. Angew. Chem. Int. Ed. 2012; 51: 8699
      CrossrefPubMed
    • 39d Lee CU, Hahne G, Hanske J, Bange T, Bier D, Rademacher C, Hennig S, Grossmann TN. Angew. Chem. Int. Ed. 2015; 54: 13796
      CrossrefPubMed
    • 39e Stiller C, Krüger DM, Brauckhoff N, Schmidt M, Janning P, Salamon H, Grossmann TN. ACS Chem. Biol. 2017; 12: 504
      CrossrefPubMed
    • 40a Mueller C, Grossmann TN. Angew. Chem. Int. Ed. 2018; 57: 17079
      CrossrefPubMed
    • 40b Brüschweiler S, Konrat R, Tollinger M. ACS Chem. Biol. 2013; 8: 1600
      CrossrefPubMed
  • 41 Kureisaite-Ciziene, D.; Varadajan, A.; McLaughlin, S. H.; Glas, M.; Montón Silva, A.; Luirink, R.; Mueller, C.; Den Blaauwen, T.; Grossmann, T. N.; Luirink, J.; Lowe, J.; MBio 2018, 9 DOI: 10.1128/mbio.01346-18.
    CrossrefPubMed
  • 42 Paulussen FM, Grossmann TN. J. Pept. Sci. 2023; 29: e3457
    CrossrefPubMed
  • 43 Schouten GK, Paulussen FM, Kuipers OP, Bitter W, Grossmann TN, van Ulsen P. Antibiotics 2022; 11: 273
    CrossrefPubMed
  • 45 Haim A, Neubacher S, Grossmann TN. ChemBioChem 2021; 22: 2672
    CrossrefPubMed
    • 46a Dang B, Wu H, Mulligan VK, Mravic M, Wu Y, Lemmin T, Ford A, Silva D.-A, Baker D, DeGrado WF. Proc. Natl. Acad. Sci. USA 2017; 114: 10852
      CrossrefPubMed
    • 46b Chen S, Bertoldo D, Angelini A, Pojer F, Heinis C. Angew. Chem. Int. Ed. 2014; 53: 1602
      CrossrefPubMed
    • 46c Heinis C, Rutherford T, Freund S, Winter G. Nat. Chem. Biol. 2009; 5: 502
      CrossrefPubMed
    • 46d Timmerman P, Beld J, Puijk WC, Meloen RH. ChemBioChem 2005; 6: 821
      CrossrefPubMed
  • 47 Neubacher S, Saya JM, Amore A, Grossmann TN. J. Org. Chem. 2019; 85: 1476
    CrossrefPubMed
  • 48 Kiehstaller S, Hutchins GH, Amore A, Gerber A, Ibrahim M, Hennig S, Neubacher S, Grossmann TN. Bioconjugate Chem. 2023; 34 (06) 1114
    CrossrefPubMed
  • 49 Hutchins GH, Kiehstaller S, Poc P, Lewis AH, Oh J, Sadighi R, Pearce NM, Ibrahim M, Drienovská I, Rijs AM. Chem 2024; 10: 615
    CrossrefPubMed
  • 50 Cheeseman JD, Tocilj A, Park S, Schrag JD, Kazlauskas RJ. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004; 60: 1237
    CrossrefPubMed
  • 51 McLoughlin NM, Mueller C, Grossmann TN. Cell Chem. Biol. 2018; 25: 19
    CrossrefPubMed