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Cited by 18Carbohydrate Chemistry and SynthesisGlycosylation and Glycoproteins ResearchChemical Synthesis and Analysis

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Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses

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Bermejo, Iris A., Guerreiro, Ana, Eguskiza, Ander, Martínez-Sáez, Nuria, Lazaris, Foivos S., Asín, Alicia, Somovilla, Víctor J., Compañón, Ismael, Raju, Tom K., Tadic, Srdan, Garrido, Pablo, García-Sanmartín, Josune, Mangini, Vincenzo, Grosso, Ana S., Marcelo, Filipa, Avenoza, Alberto, Busto, Jesús H., García-Martín, Fayna, Hurtado-Guerrero, Ramón, Peregrina, Jesús M., Bernardes, Gonçalo J. L., Martínez, Alfredo, Fiammengo, Roberto, Corzana, Francisco·2024·JACS Au
DOI 10.1021/jacsau.3c00587PMC PMC10807005
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Abstract

High Resolution Image Download MS PowerPoint Slide Mucin-1 (MUC1) glycopeptides are exceptional candidates for potential cancer vaccines. However, their autoantigenic nature often results in a weak immune response. To overcome this drawback, we carefully engineered synthetic antigens with precise chemical modifications. To be effective and stimulate an anti-MUC1 response, artificial antigens must mimic the conformational dynamics of natural antigens in solution and have an equivalent or higher binding affinity to anti-MUC1 antibodies than their natural counterparts. As a proof of concept, we have developed a glycopeptide that contains noncanonical amino acid (2 S,3 R )-3-hydroxynorvaline. The unnatural antigen fulfills these two properties and effectively mimics the threonine-derived antigen. On the one hand, conformational analysis in water shows that this surrogate explores a landscape similar to that of the natural variant. On the other hand, the presence of an additional methylene group in the side chain of this analog compared to the threonine residue enhances a CH/π interaction in the antigen/antibody complex. Despite an enthalpy–entropy balance, this synthetic glycopeptide has a binding affinity slightly higher than that of its natural counterpart. When conjugated with gold nanoparticles, the vaccine candidate stimulates the formation of specific anti-MUC1 IgG antibodies in mice and shows efficacy comparable to that of the natural derivative. The antibodies also exhibit cross-reactivity to selectively target, for example, human breast cancer cells. This investigation relied on numerous analytical (e.g., NMR spectroscopy and X-ray crystallography) and biophysical techniques and molecular dynamics simulations to characterize the antigen–antibody interactions. This workflow streamlines the synthetic process, saves time, and reduces the need for extensive, animal-intensive immunization procedures. These advances underscore the promise of structure-based rational design in the advance of cancer vaccine development.

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Metadata

Authors
Bermejo, I. A., Guerreiro, A., Eguskiza, A., Martínez-Sáez, N., Lazaris, F. S., Asín, A., Somovilla, V. J., Compañón, I., Raju, T. K., Tadic, S., Garrido, P., García-Sanmartín, J., Mangini, V., Grosso, A. S., Marcelo, F., Avenoza, A., Busto, J. H., García-Martín, F., Hurtado-Guerrero, R., Peregrina, J. M., Bernardes, G. J. L., Martínez, A., Fiammengo, R., & Corzana, F.
Affiliations
  • Universidad de La Rioja (ES)
  • University of Lisbon (PT)
  • University of Verona (IT)
  • Department of Chemistry and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Universidad de La Rioja, Logroño 26006, Spain
  • Center for Biomedical Research of La Rioja (ES)
  • Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño 26006, Spain
  • Italian Institute of Technology (IT)
  • Unidade em Ciências Biomoleculares Aplicadas (PT)
  • Institute of Biocomputation and Physics of Complex Systems, University of Zaragoza, Zaragoza 50018, Spain
Corresponding author
  • Bernardes, Gonçalo J. L.
  • Fiammengo, Roberto
  • Corzana, Francisco
ORCID
Venue
JACS Au
Publisher
American Chemical Society (ACS)
Published
2023-11-21
Volume
4
Issue
1
Pages
150-163
ISSN
2691-3704 (ISSN-L)
DOI
10.1021/jacsau.3c00587
PMC
PMC10807005
OpenAlex
W4388861006
Cited by
18
References
61
Citations by year
2026: 5 · 2025: 6 · 2024: 6 · 2023: 1
FWCI
1.78
Type
journal article
Language
en
Open access
Licence
Locations
  • JACS Au (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • RIUR (Universidad de La Rioja) (submittedVersion, other-oa)
  • Zaguan (Universidad de Zaragoza) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
Funders
  • Gobierno de Arag?n (E34_R17, LMP58_18)
  • Agencia Estatal de Investigaci?n (PID2019-105451GB-I00, PID2021-127622OB- I00, BFU201675633-P, PDC2022-133725-C21, PID2022-136735OB-I00)
  • European Regional Development Fund
  • H2020 Marie Sklodowska-Curie Actions (956544)
  • European Cooperation in Science and Technology (CA18103)
  • Funda??o para a Ci?ncia e a Tecnologia (ROTEIRO/0031/2013PINFRA/ 22161/2016, SFRH/BD/140394/2018, COVID/BD/152986/2023, 2020.00233.CEECIND, PTDC/BIA-MIB/31028/2017)
  • Applied Molecular Biosciences Unit (UIDP/04378/2020, UIDB/04378/2020)
  • Fundaci?n Agencia Aragonesa para la Investigaci?n y el Desarrollo
  • Universidad de La Rioja (REGI22/47, REGI22/16)
  • Mizutani Foundation for Glycoscience (220115)
  • Associate Laboratory Institute for Health and Bioeconomy (LA/P/0140/2020)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
MUC1 glycopeptide, cancer vaccines, structure-guided design, synthetic glycopeptides, unnatural amino acids, conformational analysis, C-H⋯π interactions, enthalpy-entropy balance, gold nanoparticle conjugates, anti-MUC1 antibodies, breast cancer, autoantigens, molecular dynamics simulation

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