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Open AccessArticle

Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding

1
Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80–308 Gdańsk, Poland
2
SIB Swiss Institute of Bioinformatics, Quartier Sorge, Bâtiment Amphipole, CH-1015 Lausanne, Switzerland
3
Urology Research Unit, Urology Department, University Hospital of Lausanne (CHUV), CH-1011 Lausanne, Switzerland
4
Intercollegiate Faculty of Biotechnology UG&MUG, University of Gdansk, Abrahama 58, 80–308 Gdańsk, Poland
5
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02–106 Warszawa, Poland
6
NanoBioMedical Center, Adam Mickiewicz University, Umultowska 85, 61–614 Poznań, Poland
7
Department of Oncology, University Hospital of Lausanne (CHUV), Ludwig Cancer Research—Lausanne Branch, CH-1011 Lausanne, Switzerland
8
Department of Oncology, University of Lausanne, Ch. des Boveresses 155, CH-1066 Lausanne, Switzerland
9
Department of Fundamental Oncology, Lausanne University, Ludwig Institute for Cancer Research, Route de la Corniche 9A, CH-1066 Epalinges, Switzerland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(2), 636; https://doi.org/10.3390/ijms21020636
Received: 5 December 2019 / Revised: 15 January 2020 / Accepted: 16 January 2020 / Published: 18 January 2020
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
Immune checkpoints are crucial in the maintenance of antitumor immune responses. The activation or blockade of immune checkpoints is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals, including the enhancement or suppression of T-cell proliferation, differentiation, and/or cytokine secretion. B-and T-lymphocyte attenuator (BTLA) is a lymphoid-specific cell surface receptor which is present on T-cells and interacts with herpes virus entry mediator (HVEM), which is present on tumor cells. The binding of HVEM to BTLA triggers an inhibitory signal which attenuates the immune response. This feature is interesting for studying the molecular interactions between HVEM and BTLA, as they may be targeted for novel immunotherapies. This work was based on the crystal structure of the BTLA/HVEM complex showing that BTLA binds the N-terminal cysteine-rich domain of HVEM. We investigated the amino acid sequence of HVEM and used molecular modeling methods to develop inhibitors of the BTLA/HVEM interaction. We synthesized novel compounds and determined their ability to interact with the BTLA protein and inhibit the formation of the BTLA/HVEM complex. Our results suggest that the HVEM (14–39) peptide is a potent inhibitor of the formation of the BTLA/HVEM protein complex. View Full-Text
Keywords: B-and T-lymphocyte attenuator; herpes virus entry mediator; immunotherapy; immune checkpoint inhibitor; disulfide-linked peptide; NMR structure; molecular docking; surface plasmon resonance B-and T-lymphocyte attenuator; herpes virus entry mediator; immunotherapy; immune checkpoint inhibitor; disulfide-linked peptide; NMR structure; molecular docking; surface plasmon resonance
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Spodzieja, M.; Kuncewicz, K.; Sieradzan, A.; Karczyńska, A.; Iwaszkiewicz, J.; Cesson, V.; Węgrzyn, K.; Zhukov, I.; Maszota-Zieleniak, M.; Michielin, O.; Speiser, D.E.; Zoete, V.; Derré, L.; Rodziewicz-Motowidło, S. Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding. Int. J. Mol. Sci. 2020, 21, 636.

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