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CC BY 4.0 · Synlett 2025; 36(02): 119-128
DOI: 10.1055/a-2308-1795
DOI: 10.1055/a-2308-1795
account
From Protein Structures to Functional Biomimetics
We 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.
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 designPublikationsverlauf
Eingereicht: 02. April 2024
Angenommen nach Revision: 16. April 2024
Accepted Manuscript online:
17. April 2024
Artikel online veröffentlicht:
08. Mai 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
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References
- 1a Marsh JA, Teichmann SA. PLoS Biol. 2014; 12: e1001870
- 1b Dobson CM, Šali A, Karplus M. Angew. Chem. Int. Ed. 1998; 37: 868
- 3a Milroy L.-G, Grossmann TN, Hennig S, Brunsveld L, Ottmann C. Chem. Rev. 2014; 114: 4695
- 3b Pelay-Gimeno M, Glas A, Koch O, Grossmann TN. Angew. Chem. Int. Ed. 2015; 54: 8896
- 3c Valeur E, Guéret SM, Adihou H, Gopalakrishnan R, Lemurell M, Waldmann H, Grossmann TN, Plowright AT. Angew. Chem. Int. Ed. 2017; 56: 10294
- 4 Lenci E, Trabocchi A. Chem. Soc. Rev. 2020; 49: 3262
- 5 Algar S, Martín-Martínez M, González-Muñiz R. Eur. J. Med. Chem. 2021; 211: 113015
- 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
- 7a Glas A, Bier D, Hahne G, Rademacher C, Ottmann C, Grossmann TN. Angew. Chem. Int. Ed. 2014; 53: 2489
- 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
- 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
- 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
- 9 Pelay-Gimeno M, Bange T, Hennig S, Grossmann TN. Angew. Chem. Int. Ed. 2018; 57: 11164
- 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
- 11b Chu Q, Moellering RE, Hilinski GJ, Kim Y.-W, Grossmann TN, Yeh JT.-H, Verdine GL. MedChemComm 2015; 6: 111
- 11c Kim Y.-W, Grossmann TN, Verdine GL. Nat. Protoc. 2011; 6: 761
- 11d Schafmeister CE, Po J, Verdine GL. J. Am. Chem. Soc. 2000; 122: 5891
- 12 Glas A, Grossmann TN. Synlett 2015; 26: 1
- 13 Glas A, Wamhoff EC, Krüger DM, Rademacher C, Grossmann TN. Chem. Eur. J. 2017; 23: 16157
- 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
- 15 Wallraven K, Holmelin FL, Glas A, Hennig S, Frolov AI, Grossmann TN. Chem. Sci. 2020; 11: 2269
- 16 Cromm PM, Wallraven K, Glas A, Bier D, Fürstner A, Ottmann C, Grossmann TN. ChemBioChem 2016; 17: 1915
- 17 Blackwell HE, Grubbs RH. Angew. Chem. Int. Ed. 1998; 37: 3281
- 18 Toniolo C, Crisma M, Formaggio F, Valle C, Cavicchioni G, Precigoux G, Aubry A, Kamphuis J. Biopolymers 1993; 33: 1061
- 19a Cromm PM, Spiegel J, Grossmann TN, Waldmann H. Angew. Chem. Int. Ed. 2015; 54: 13516
- 19b Spiegel J, Cromm PM, Zimmermann G, Grossmann TN, Waldmann H. Nat. Chem. Biol. 2014; 10: 613
- 20 Spiegel J, Cromm PM, Itzen A, Goody RS, Grossmann TN, Waldmann H. Angew. Chem. Int. Ed. 2014; 53: 2498
- 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
- 22 Cromm PM, Schaubach S, Spiegel J, Fürstner A, Grossmann TN, Waldmann H. Nat. Commun. 2016; 7: 11300
- 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
- 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
- 25 Durukan C, Arbore F, Klintrot R, Bigiotti C, Ilie IM, Vreede J, Grossmann TN, Hennig S. ChemBioChem 2024; e202400020
- 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
- 27a Koelman EM, Yeste-Vázquez A, Grossmann TN. Bioorg. Med. Chem. 2022; 70: 116920
- 27b Hahne G, Grossmann TN. Bioorg. Med. Chem. 2013; 21: 4020
- 28 McCoy MA, Spicer D, Wells N, Hoogewijs K, Fiedler M, Baud MG. J. Med. Chem. 2022; 65: 7246
- 29 Grossmann TN, Yeh JT.-H, Bowman BR, Chu Q, Moellering RE, Verdine GL. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 17942
- 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
- 31 Dietrich L, Rathmer B, Ewan K, Bange T, Heinrichs S, Dale TC, Schade D, Grossmann TN. Cell Chem. Biol. 2017; 24: 958
- 32 Huber AH, Weis WI. Cell 2001; 105: 391
- 33a Ellenbroek B, Kahler JP, Evers SR, Pomplun SJ. Angew. Chem. Int. Ed. 2024; e202401704
- 33b Pal S, tHart P. Front. Mol. Biosci. 2022; 9: 883060
- 34 Chen HY, Yang J, Lin C, Yuan YA. EMBO Rep. 2008; 9: 754
- 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
- 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
- 37 McLoughlin NM, Kuepper A, Neubacher S, Grossmann TN. Chem. Eur. J. 2021; 27: 10477
- 38 Shiraiwa K, Cheng R, Nonaka H, Tamura T, Hamachi I. Cell Chem. Biol. 2020; 27: 970
- 39a Brauckhoff N, Fang L, Haim A, Grossmann TN. Chem. Commun. 2023; 59: 5241
- 39b Brauckhoff N, Hahne G, Yeh JT. H, Grossmann TN. Angew. Chem. Int. Ed. 2014; 53: 4337
- 39c Lee CU, Grossmann TN. Angew. Chem. Int. Ed. 2012; 51: 8699
- 39d Lee CU, Hahne G, Hanske J, Bange T, Bier D, Rademacher C, Hennig S, Grossmann TN. Angew. Chem. Int. Ed. 2015; 54: 13796
- 39e Stiller C, Krüger DM, Brauckhoff N, Schmidt M, Janning P, Salamon H, Grossmann TN. ACS Chem. Biol. 2017; 12: 504
- 40a Mueller C, Grossmann TN. Angew. Chem. Int. Ed. 2018; 57: 17079
- 40b Brüschweiler S, Konrat R, Tollinger M. ACS Chem. Biol. 2013; 8: 1600
- 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
- 42 Paulussen FM, Grossmann TN. J. Pept. Sci. 2023; 29: e3457
- 43 Schouten GK, Paulussen FM, Kuipers OP, Bitter W, Grossmann TN, van Ulsen P. Antibiotics 2022; 11: 273
- 44a Magliery TJ. Curr. Opin. Struct. Biol. 2015; 33: 161
- 44b Chapman AM, McNaughton BR. Cell Chem. Biol. 2016; 23: 543
- 44c Reetz MT. Angew. Chem. Int. Ed. 2013; 52: 2658
- 45 Haim A, Neubacher S, Grossmann TN. ChemBioChem 2021; 22: 2672
- 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
- 46b Chen S, Bertoldo D, Angelini A, Pojer F, Heinis C. Angew. Chem. Int. Ed. 2014; 53: 1602
- 46c Heinis C, Rutherford T, Freund S, Winter G. Nat. Chem. Biol. 2009; 5: 502
- 46d Timmerman P, Beld J, Puijk WC, Meloen RH. ChemBioChem 2005; 6: 821
- 47 Neubacher S, Saya JM, Amore A, Grossmann TN. J. Org. Chem. 2019; 85: 1476
- 48 Kiehstaller S, Hutchins GH, Amore A, Gerber A, Ibrahim M, Hennig S, Neubacher S, Grossmann TN. Bioconjugate Chem. 2023; 34 (06) 1114
- 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
- 50 Cheeseman JD, Tocilj A, Park S, Schrag JD, Kazlauskas RJ. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004; 60: 1237
- 51 McLoughlin NM, Mueller C, Grossmann TN. Cell Chem. Biol. 2018; 25: 19