Gangliosides, sialylated glycosphingolipids abundant in the nervous system, play crucial roles in neurotransmission, interaction with regulatory proteins, cell-cell recognition, and signaling. Altered gangliosides expression has been correlated with pathological processes, including cancer, inflammatory disorders, and autoimmune diseases. Gangliosides are important endogenous ligands of Siglecs (Sialic acid-binding immunoglobulin-type lectins), I-type lectins mostly expressed by immune cells, that specifically recognize sialylated glycans. Siglec-7, an inhibitory immune receptor on human natural killer cells, represents a potential target for tumor immunotherapy. Notably, the expression of Siglec-7 ligands is high in various cancers, such as pancreatic cancer and melanoma and lead to tumor immune evasion. Siglec-7 binds the disialylated ganglioside GD3, a tumor-associated antigen overexpressed on cancer cells to suppress immune responses. Using a combination of structural biology techniques, including Nuclear Magnetic Resonance (NMR), biophysical, and computational methods, the binding of Siglec-7 to GD3 and Gb3 derivatives is investigated, revealing the importance of ligand conformation in modulating binding energetics and affinity. The greater flexibility of Gb3 derivatives appears to negatively impact binding entropy, leading to lower affinity compared to GD3. A thorough understanding of these interactions could contribute to elucidating molecular mechanisms of cancer immune evasion and facilitate the development of ganglioside-based diagnostic and therapeutic strategies for cancer.

CEINGE Biotecnologie Avanzate Franco Salvatore Via Gaetano Salvatore 486 Napoli 80145 Italy

Department of Biochemistry Faculty of Science Charles University Hlavova 2030 8 Prague 12800 Czech Republic

Department of Chemical Sciences University of Naples Federico 2 Via Cinthia 4 Naples 80126 Italy

Department of Chemistry National Tsing Hua University Hsinchu 300044 Taiwan

Department of Medicinal and Applied Chemistry Kaohsiung Medical University Kaohsiung 80708 Taiwan

Giotto Biotech s r l Sesto Fiorentino 50019 Italy

Magnetic Resonance Centre CIRMMP and Department of Chemistry Ugo Schiff University of Florence Via Luigi Sacconi 6 Sesto Fiorentino 50019 Italy

Zobrazit více v PubMed

Schauer R., Kamerling J. P., Adv. Carbohydr. Chem. Biochem. 2018, 75, 1. PubMed PMC

Di Carluccio C., Forgione R. E., Molinaro A., Crocker P. R., Marchetti R., Silipo A., Carbohydr. Chem. 2021, 44, 31.

Varki A., Cummings R. D., Esko J. D., Stanley P., Hart G. W., Aebi M., Darvill A. G., Kinoshita T., Packer N. H., Prestegard J. H., Schnaar R. L., Seeberger P. H., Essentials of Glycobiology, 4th ed., Cold Spring Harbor Laboratory Press, New York: 2017. PubMed

Groux‐Degroote S., Guérardel Y., Julien S., Delannoy P., Biochemistry (Moscow) 2015, 80, 808. PubMed

Schnaar R. L., Glycoconjugate J. 2023, 40, 159. PubMed PMC

Schnaar R. L., J. Mol. Biol. 2016, 428, 3325. PubMed PMC

Schnaar R. L., Gerardy‐Schahn R., Hildebrandt H., Physiol. Rev. 2014, 94, 461. PubMed PMC

Ohmi Y., Tajima O., Ohkawa Y., Yamauchi Y., Sugiura Y., Furukawa K., Furukawa K., J. Neurochem. 2011, 116, 926. PubMed

Furukawa K., Kambe M., Miyata M., Ohkawa Y., Tajima O., Furukawa K., Cancer Sci. 2014, 105, 52. PubMed PMC

Rodrigues E., Macauley M. S., Cancers 2018, 10, 207. PubMed PMC

Bordoloi D., Kulkarni A. J., Adeniji O. S., Betina Pampena M., Bhojnagarwala P. S., Zhao S., Ionescu C., Perales‐Puchalt A., Parzych E. M., Zhu X., Ali A. R., Cassel J., Zhang R., Betts M. R., Abdel‐Mohsen M., Weiner D. B., Sci. Adv. 2023, 9, adh4379. PubMed PMC

van de Wall S., Santegoets K. C. M., van Houtum E. J. H., Büll C., Adema G. J., Trends Immunol. 2020, 41, 274. PubMed

Krengel U., Bousquet P. A., Front. Immunol. 2014, 5, 325. PubMed PMC

Ito A., Handa K., Withers D. A., Satoh M., itiroh Hakomori S., FEBS Lett. 2001, 504, 82. PubMed

Yamaji T., Teranishi T., Alphey M. S., Crocker P. R., Hashimoto Y., J. Biol. Chem. 2002, 277, 6324. PubMed

Ramos R. I., Bustos M. A., Wu J., Jones P., Chang S. C., Kiyohara E., Tran K., Zhang X., Stern S. L., Izraely S., Sagi‐Assif O., Witz I. P., Davies M. A., Mills G. B., Kelly D. F., Irie R. F., Hoon D. S. B., Mol. Oncol. 2020, 14, 1760. PubMed PMC

Malisan F., Testi R., BBA ‐ Mol. Cell Biol. Lipids 2002, 1585, 179. PubMed

Webb T. J., Li X., Giuntoli R. L., Lopez P. H. H., Heuser C., Schnaar R. L., Tsuji M., Kurts C., Oelke M., Schneck J. P., Cancer Res. 2012, 72, 3744. PubMed PMC

Bärenwaldt A., Läubli H., Expert Opin. Ther. Targets 2019, 23, 839. PubMed

Daly J., Carlsten M., O'Dwyer M., Front. Immunol. 2019, 10, 1047. PubMed PMC

Liu J., Zheng X., Pang X., Li L., Wang J., Yang C., Du G., Acta Pharm. Sin. B 2018, 8, 713. PubMed PMC

Li P., Huang S., Chiang P., Fan C., Guo L., Wu D., Angata T., Lin C., Angew. Chem., Int. Ed. 2019, 131, 11395. PubMed

Kim C. H., Ganglioside Biochemistry, Springer, New York, NY: 2020, pp. 1–13.

Nepravishta R., Ramírez‐Cárdenas J., Rocha G., Walpole S., Hicks T., Monaco S., Muñoz‐García J. C., Angulo J., J. Med. Chem. 2024, 67, 10025. PubMed PMC

Abreu C., Di Carluccio C., Ječmen T., Skořepa O., Bláha J., Marchetti R., Silipo A., Vaněk O., Int. J. Biol. Macromol. 2025, 309, 142672. PubMed

Forgione R. E., Di Carluccio C., Guzmán‐Caldentey J., Gaglione R., Battista F., Chiodo F., Manabe Y., Arciello A., Del Vecchio P., Fukase K., Molinaro A., Martín‐Santamaría S., Crocker P. R., Marchetti R., Silipo A., iScience 2020, 23, 101401. PubMed PMC

Oliva R., Jahmidi‐Azizi N., Mukherjee S., Winter R., J. Phys. Chem. B 2021, 125, 539. PubMed

Nieto‐Fabregat F., Lenza M. P., Marseglia A., Di Carluccio C., Molinaro A., Silipo A., Marchetti R., Beilstein J. Org. Chem. 2024, 20, 2084. PubMed PMC

Soares C. O., Grosso A. S., Ereño‐Orbea J., Coelho H., Marcelo F., Front. Mol. Biosci. 2021, 8, 727847. PubMed PMC

Di Carluccio C., Forgione R. E., Bosso A., Yokoyama S., Manabe Y., Pizzo E., Molinaro A., Fukase K., Fragai M., Bensing B. A., Marchetti R., Silipo A., RSC Chem. Biol. 2021, 2, 1618. PubMed PMC

Di Carluccio C., Crisman E., Manabe Y., Forgione R. E., Lacetera A., Amato J., Pagano B., Randazzo A., Zampella A., Lanzetta R., Fukase K., Molinaro A., Crocker P. R., Martín‐Santamaría S., Marchetti R., Silipo A., ChemBioChem 2020, 21, 129. PubMed

Forgione R. E., Di Carluccio C., Kubota M., Manabe Y., Fukase K., Molinaro A., Hashiguchi T., Marchetti R., Silipo A., Sci. Rep. 2020, 10, 1589. PubMed PMC

Li P., Huang S., Chiang P., Fan C., Guo L., Wu D., Angata T., Lin C., Angew. Chem., Int. Ed. 2019, 58, 11273. PubMed

Liu Y., Yan M., Wang M., Luo S., Wang S., Luo Y., Xu Z., Ma W., Wen L., Li T., ACS Cent. Sci. 2024, 10, 417. PubMed PMC

Groux‐Degroote S., Delannoy P., Int. J. Mol. Sci. 2021, 22, 6145. PubMed PMC

Li Q., Sun M., Yu M., Fu Q., Jiang H., Yu G., Li G., Glycoconjugate J. 2019, 36, 419. PubMed

Iltis C., Seguin L., Cervera L., Duret L., Hamidouche T., Kunz S., Croce O., Delannoy C., Gueŕardel Y., Allain F., Moudombi L., Hofman P., Cosson E., Guglielmi J., Pourcher T., Braud V. M., Shkreli M., Michallet M. C., Feral C. C., Gilson E., Cherfils‐Vicini J., bioRxiv 2021, 440408.

Hashimoto N., Ito S., Tsuchida A., Bhuiyan R. H., Okajima T., Yamamoto A., Furukawa K., Ohmi Y., Furukawa K., J. Biol. Chem. 2019, 294, 10833. PubMed PMC

Attrill H., Imamura A., Sharma R. S., Kiso M., Crocker P. R., Van Aalten D. M. F., J. Biol. Chem. 2006, 281, 32774. PubMed

Yamakawa N., Yasuda Y., Yoshimura A., Goshima A., Crocker P. R., Vergoten G., Nishiura Y., Takahashi T., Hanashima S., Matsumoto K., Sci. Rep. 2020, 10, 8647. PubMed PMC

Yoshimura A., Hatanaka R., Tanaka H., Kitajima K., Sato C., Biochem. Biophys. Res. Commun 2021, 534, 1069. PubMed

Cavdarli S., Delannoy P., Groux‐Degroote S., Cells 2020, 9, 741. PubMed PMC

Tong W., Maira M., Roychoudhury R., Galan A., Brahimi F., Gilbert M., Cunningham A. M., Josephy S., Pirvulescu I., Moffett S., Saragivi H. U., Cell Chem. Biol. 2019, 26, 1013. PubMed

Di Carluccio C., Milanesi F., Civera M., Abreu C., Sattin S., Francesconi O., Molinaro A., Vaněk O., Marchetti R., Silipo A., Eur. J. Org. Chem. 2023, 26, 202300644.

Pröpster J. M., Yang F., Ernst B., Allain F. H. T., Schubert M., Protein Expression Purif. 2015, 109, 14. PubMed

Keller R., The Computer Aided Resonance Assignment, CANTINA Verlag, Germany: 2004.

Williamson M. P., Prog. Nucl. Magn. Reson. Spectrosc. 2013, 73, 1. PubMed

Giuntini S., Balducci E., Cerofolini L., Ravera E., Fragai M., Berti F., Luchinat C., Angew. Chem. 2017, 129, 15193. PubMed PMC

Mayer M., Meyer B., J. Am. Chem. Soc. 2001, 123, 6108. PubMed

Meyer B., Peters T., Angew. Chem. – Int. Ed. 2003, 42, 864. PubMed

Ribeiro M. M. B., Franquelim H. G., Castanho M. A. R. B., Veiga A. S., J. Pept. Sci. 2008, 14, 401. PubMed

Jahmidi‐azizi N., Gault S., Cockell C. S., Oliva R., Winter R., Int. J. Mol. Sci. 2021, 22, 10861. PubMed PMC

GLYCAM‐Web. Utilities for molecular modeling of carbohydrates Woods Group; (2005‐2024) (accessed: April 2025), http://glycam.org.

Case D. A., Ben‐Shalom I. Y., Brozell S. R., Cerutti D. S., Cheatham T. E. III, Cruzeiro V. W. D., Darden T. A., Duke R. E., Ghoreishi D., Gilson M. K., Gohlke H., Goetz A. W., Greene D., Harris R., Homeyer N., Huang Y., Izadi S., Kovalenko A., Kurtzman T., Lee T. S., LeGrand S., Li P., Lin C., Liu J., Luchko T., Luo R., Mermelstein D. J., Merz K. M., Miao Y., Monard G., et al., AMBER, University of California, San Francisco: 2018.

Roe D. R., Cheatham T. E., J. Chem. Theory Comput. 2013, 9, 3084. PubMed

Molecular Basis of Siglec‑7 Recognition by Neisseria meningitidis Serogroup Y CPS: Implications for Immune Evasion