Disulfide-linked peptides for blocking BTLA/HVEM binding

Marta Spodzieja , Katarzyna Kuncewicz , Adam Sieradzan , Agnieszka Karczyńska , Justyna Iwaszkiewicz , Valérie Cesson , Katarzyna Węgrzyn , Igor Zhukov , Martyna Maszota-Zieleniak , Olivier Michielin , Daniel E. Speiser , Vincent Zoete , Laurent Derre , Sylwia Rodziewicz-Motowidło

Abstract

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, dierentiation, 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.
Author Marta Spodzieja (FCh / DBCh / LMCh)
Marta Spodzieja,,
- Laboratory of Medical Chemistry
, Katarzyna Kuncewicz (FCh / DBCh / LMCh)
Katarzyna Kuncewicz,,
- Laboratory of Medical Chemistry
, Adam Sieradzan (FCh / DTCh / LMM)
Adam Sieradzan,,
- Laboratory of Molecular Modeling
, Agnieszka Karczyńska (FCh / DTCh / LMM)
Agnieszka Karczyńska,,
- Laboratory of Molecular Modeling
, Justyna Iwaszkiewicz
Justyna Iwaszkiewicz,,
-
, Valérie Cesson
Valérie Cesson,,
-
, Katarzyna Węgrzyn (IFB / M020 / DMCB)
Katarzyna Węgrzyn,,
- Department of Molecular and Cellular Biology
, Igor Zhukov
Igor Zhukov,,
-
, Martyna Maszota-Zieleniak (FCh / DBCh / LMCh)
Martyna Maszota-Zieleniak,,
- Laboratory of Medical Chemistry
, Olivier Michielin
Olivier Michielin,,
-
et al.`
Journal seriesInternational Journal of Molecular Sciences, ISSN 1422-0067, (N/A 140 pkt)
Issue year2020
Vol21
No2
Pages1-18
Publication size in sheets0.85
Article number636
Keywords in EnglishB-and T-lymphocyte attenuator, herpes virus entry mediator, immunotherapy, immune checkpoint inhibitor, disulfide-linked peptide, NMR structure, molecular docking, surface plasmon resonance
ASJC Classification2700 General Medicine; 1312 Molecular Biology; 1503 Catalysis; 1604 Inorganic Chemistry; 1605 Organic Chemistry; 1606 Physical and Theoretical Chemistry; 1607 Spectroscopy; 1706 Computer Science Applications
DOIDOI:10.3390/ijms21020636
URL https://doi.org/10.3390/ijms21020636
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 28-02-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.224; WoS Impact Factor: 2018 = 4.183 (2) - 2018=4.331 (5)
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