Title: De novo designed, structurally extended peptide foldamers and their use for construction of PD-1/PD-L1 interaction inhibitors

Founding: NCN OPUS, 2018/31/B/ST5/02631

Budget: 2 364 600 PLN

PI: Łukasz Berlicki

Team: Ewa Rudzińska-Szostak, Katarzyna Ożga, Srinivasa Rao Nelli, Monika Szefczyk, Agnieszka Ciesiołkiewicz, Juan Lizandra Perez, Paweł Morawiak

Abstract

Peptide foldamers constitute an emerging class of compounds, which is defined as oligomers with high tendency to form compact conformations in solution. alpha/beta-Peptides containing constrained beta-amino acids are one of the most promising group of peptide foldamers due to the possibility of rational design of secondary structures and the possibility of incorporation of chosen functions. Although, numerous studies on peptide foldamers have been published, a general strategy of construction of structurally extended peptide foldamers containing tertiary structures is still missing. alpha/beta-Peptide foldamers exhibit also several advantages for building biologically active compounds including: high proteolytic stability, biocompatibility, and possibility of incorporation of various non-canonical amino acids.
The main goals of this project are: (1) the development of computer-aided methodology for de novo construction of structurally extended peptide foldamers of chosen geometry, and (2) the application of created structures as scaffolds for building effective inhibitors of chosen protein-protein interactions, namely PD-1/PD-L1, which could be useful for cancer immunotherapy.

There are numerous innovative aspect of this project which will impact various branches of science. Better understanding of protein folding principles will be achieved by studies on structurally extended peptide foldamers containing tertiary structures. Structural insight in three-dimensional arrangements formed by alpha/beta-peptides will be also made. The developed methodology of building structurally complex molecules with feasible synthesis could find several applications in various fields of science and technology, including: medicinal chemistry, catalysis, material science and nanotechnology. In particular, the use of structurally extended peptide foldamers for the development of protein-protein interaction inhibitors will be evaluated. This approach will be considerably valuable in the most problematic cases where no specific binding clefts in protein targets are present. Finally, the found PD-1/PD-L1 interaction inhibitors could find the application for cancer immunotherapy.

Publications

1. Berlicki, Ł. Tailoring peptides and peptidomimetics for targeting protein-protein interactions, in Peptide and Peptidomimetic Therapeutics: From Bench to Bedside, 2022, 57-71, Elsevier - Academic Press
2. Ciesiołkiewicz, A.; Lizandra Perez, J.; Berlicki, Ł. Miniproteins in Medicinal Chemistry, Bioorg. Med. Chem. Lett. 2022, 128806.
3. Ciesiołkiewicz, A.; Lizandra Perez, J.; Skalniak, L.; Noceń, P.; Berlicki, Ł. Miniprotein engineering for inhibition of PD‐1/PD‐L1 interaction, Protein Sci. 2024, 33, e5106. View at Publisher
4. Kovalenko, V.; Rudzińska-Szostak, E.; Ślepokura, K.; Berlicki, Ł. Scalable Synthesis of All Stereoisomers of 2-Aminocyclopentanecarboxylic Acid─A Toolbox for Peptide Foldamer Chemistry. J Org Chem 2024, 89 (7), 4760–4767. View at Publisher.

Conference Communications

1. Ł. Berlicki, Design and engineering of conformationally constrained mini-proteins, Symposium on Foldamers, Bordeaux 2021, invited lecture.
2. J. Lizandra Perez, Ł. Berlicki, From WW-domains to foldameric miniproteins, suitable scaffolds for PD-1/PD-L1 interaction inhibitors. ChemBiotIC, , Wrocław, 2021, poster.
3. A. Ciesiołkiewicz, K. Ożga, Ł. Berlicki, Optimization of foldameric scaffold based on EEHEE motif and its use for construction of PD-1/PD-L1 inhibitors, ChemBiotIC, 2021, poster.
4. P. Noceń, Ł. Berlicki, An approach to design and synthesize miniproteins binding to PD-1 receptor, ChemBiotIC, Wrocław 2021, poster.
5. J. Lizandra Perez, Ł. Berlicki, WW-domain based inhibitors of pd-1/pdl-1 interaction. XXVI EFMC International Symposium on Medicinal Chemistry, online 2021, poster.
6. A. Ciesiołkiewicz, K. Ożga, Ł. Berlicki, De novo design of foldameric mini-proteins and their use as PD-1/PD-L1 interaction inhibitors, XXVI EFMC International Symposium on Medicinal Chemistry 2021, online 2021, poster.
7. P. Noceń, Ł. Berlicki, Novel PD-1-targeted inhibitors of PD-1/PD-L1 interaction designed basing on the MvaT miniprotein structure, XXVI EFMC International Symposium on Medicinal Chemistry 2021, online 2021, poster.
8. K. Ożga, A. Ciesiołkiewicz, Ł. Berlicki, The design on novel foldameric mini-proteins and their use in the construction of PD-1/PD-L1 interaction inhibitors, RSC Chemical Biology Syposium, online 2021, poster.
9. J. Lizandra Perez, Ł. Berlicki, De novo foldameric miniprotein as inhibitors of PD-1/PD-L1 interaction, Interdisciplinary Conference on Drug Sciences, Warszawa 2022, poster.
10. A. Ciesiołkiewicz, Ł. Berlicki, Miniprotein-based PD-1/PD-L1 interaction inhibitors, Interdisciplinary Conference on Drug Sciences, Warszawa 2022, poster.
11. Ł. Berlicki, Design and engineering of miniproteins - towards functional molecules, Hungarian Peptide Society Meeting, Balatonszemes, 2022, wykład zaproszony.
12. P Noceń, Ł. Berlicki, Synthesis and inhibitory activity of PD-1-targeted peptides derived from sequences of MvaT and ENH miniproteins. 64th PTChem , Lublin 2022, poster.
13. A. Ciesiołkiewicz, Ł. Berlicki, Mini-białkowe inhibitory oddziaływania PD-1/PD-L1 jako nowe podejście w immunoterapii przeciwnowotworowej, Na Pograniczu Chemii i Biologii XIX, Trzebieszowice, 4-7.06.2023; prezentacja ustna.
14. Ł. Berlicki, Exploring Miniproteins — Structures and Functions, American Peptide Symposium, Scottsdale 2023, poster.
15. J. Lizandra Pérez, Ł. Berlicki, β-Amino Acid Containing Miniproteins as Scaffolds for PD-1/PD-L1 Interaction Inhibitors, American Peptide Symposium, Scottsdale 2023, poster.
16. E. Rudzińska-Szostak, K. Ożga, M. Kołacki, and Ł. Berlicki, Design, Synthesis and Spectral Analysis of Miniproteins Containing π-Cation Stabilized β-Hairpin and Non-Canonical Helix, , American Peptide Symposium, Scottsdale 2023, poster.
17. A. Ciesiołkiewicz, J.Lizandra Perez, Ł. Skalniak, Ł. Berlicki, Novel PD-1/PD-L1 interaction inhibitors based on the engrailed homeodomain miniprotein scaffold, American Peptide Symposium, Scottsdale 2023, poster.
18. P. Noceń, Ł. Berlicki, Validation of the choice of a miniprotein scaffold used for the obtainment of inhibitors targeted towards PD-1 protein, ChemBiotIC, Wrocław 2023, poster.