In Silico Design of Novel Mutant Anti-MUC1 Aptamers for Targeted Cancer Therapy

Brianda L. Santini, Matías Zúñiga-Bustos, Abraham Vidal-Limon, Joel B. Alderete, Sergio A. Águila, Verónica A. Jiménez

Resultado de la investigación: Article

Resumen

The transmembrane glycoprotein mucin 1 (MUC1) is an attractive tumor marker for cancer therapy and diagnosis. The nine amino acid extracellular epitope APDTRPAPG of this protein is selectively recognized by the S2.2 single-stranded DNA anti-MUC1 aptamer, which has emerged as a promising template for designing novel targeting agents for MUC1-directed therapy. In this work, 100 ns molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, and conformational analysis were employed to propose a novel prospective anti-MUC1 aptamer with increased affinity toward the MUC1 epitope resulting from the double mutation of the T11 and T12 residues with PSU and U nucleosides, respectively. The double mutant aptamer exhibits a tight interaction with the MUC1 epitope and adopts a groove conformation that structurally favors the intermolecular contact with the epitope through the intermediate T11-A18 region leaving the 3′ and 5′ ends free for further chemical conjugation with a nanocarrier or pharmaceutical. These results are valuable to gain understanding about the molecular features governing aptamer-epitope interactions and constitute a first key step for the design of novel aptamer-based nanocarriers for MUC1-targeted cancer therapy.

Idioma originalEnglish
PublicaciónJournal of Chemical Information and Modeling
DOI
EstadoAccepted/In press - 1 nov 2019

Huella dactilar

Epitopes
Mucin-1
cancer
interaction
pharmaceutical
Glycoproteins
contact
energy
simulation
Drug products
Free energy
Conformations
Molecular dynamics
Amino acids
Single-Stranded DNA
DNA
Tumor Biomarkers
Nucleosides
Proteins
Computer simulation

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Citar esto

Santini, Brianda L. ; Zúñiga-Bustos, Matías ; Vidal-Limon, Abraham ; Alderete, Joel B. ; Águila, Sergio A. ; Jiménez, Verónica A. / In Silico Design of Novel Mutant Anti-MUC1 Aptamers for Targeted Cancer Therapy. En: Journal of Chemical Information and Modeling. 2019.
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abstract = "The transmembrane glycoprotein mucin 1 (MUC1) is an attractive tumor marker for cancer therapy and diagnosis. The nine amino acid extracellular epitope APDTRPAPG of this protein is selectively recognized by the S2.2 single-stranded DNA anti-MUC1 aptamer, which has emerged as a promising template for designing novel targeting agents for MUC1-directed therapy. In this work, 100 ns molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, and conformational analysis were employed to propose a novel prospective anti-MUC1 aptamer with increased affinity toward the MUC1 epitope resulting from the double mutation of the T11 and T12 residues with PSU and U nucleosides, respectively. The double mutant aptamer exhibits a tight interaction with the MUC1 epitope and adopts a groove conformation that structurally favors the intermolecular contact with the epitope through the intermediate T11-A18 region leaving the 3′ and 5′ ends free for further chemical conjugation with a nanocarrier or pharmaceutical. These results are valuable to gain understanding about the molecular features governing aptamer-epitope interactions and constitute a first key step for the design of novel aptamer-based nanocarriers for MUC1-targeted cancer therapy.",
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In Silico Design of Novel Mutant Anti-MUC1 Aptamers for Targeted Cancer Therapy. / Santini, Brianda L.; Zúñiga-Bustos, Matías; Vidal-Limon, Abraham; Alderete, Joel B.; Águila, Sergio A.; Jiménez, Verónica A.

En: Journal of Chemical Information and Modeling, 01.11.2019.

Resultado de la investigación: Article

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AU - Vidal-Limon, Abraham

AU - Alderete, Joel B.

AU - Águila, Sergio A.

AU - Jiménez, Verónica A.

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