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

Santini B.L.; Zúñiga-Bustos M.; Vidal-Limon A.; Alderete J.B.; Águila S.A.; Jiménez V.A.

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.

Más información

Título según WOS: In Silico Design of Novel Mutant Anti-MUC1 Aptamers for Targeted Cancer Therapy
Título según SCOPUS: In Silico Design of Novel Mutant Anti-MUC1 Aptamers for Targeted Cancer Therapy
Volumen: 60
Número: 2
Fecha de publicación: 2020
Página de inicio: 786
Página final: 793
Idioma: English
DOI:

10.1021/acs.jcim.9b00756

Notas: ISI, SCOPUS