A combined experimental and computational study on peptide nucleic acid (PNA) analogues of tumor suppressive miRNA-34a(52 visite) Piacenti V, Langella E, Autiero I, Nolan JC, Piskareva O, Adamo MFA, Saviano M, Moccia M
Parole chiave: Mirna-34a, Molecular Dynamics, Pna, Tumor Suppressive,
*** IBB - CNR *** RCSI, Dept. of Pharmaceutical & Medicinal Chemistry, 123 St Stephen's Green, Dublin 2, Ireland., National Research Council (CNR)-IBB, via Mezzocannone 16, 80134 Naples, Italy., RCSI, Dept. of Cancer Genetics, York Street, Dublin 2, Ireland., National Research Council (CNR)-IC, via G. Amendola 122/O, 70126 Bari, Italy., National Research Council (CNR)-IC, via G. Amendola 122/O, 70126 Bari, Italy. Electronic address: firstname.lastname@example.org.,
MicroRNAs are a ubiquitous class of non-coding RNAs able to regulate gene expression in diverse biological processes. Widespread miRNAs deregulation was reported in numerous diseases including cancer, with several miRNAs playing oncogenic and/or tumor suppressive role by targeting multiple mRNAs simultaneously. Based on these findings, miRNAs have emerged as promising therapeutic tools for cancer treatment. Herein, for the first time, peptide nucleic acids (PNAs) were studied to develop a new class of molecules able to target 3'UTR on MYCN mRNA without a fully complementary base pairing sequence (as miRNAs). For our proof of concept study we have selected as a model the miRNA-34a, which acts as a tumor suppressor in a number of cancers including neuroblastoma. In particular, miRNA-34a is a direct regulator of MYCN oncogene, whose overexpression is a prominent biomarker for the highly aggressive neuroblastoma phenotype. The design and synthesis of three PNA-based oligomers of different length was described, and their interaction with two binding sites on the target MYCN mRNA was investigated by molecular dynamics simulation, and spectroscopic techniques (CD, UV). Intake assay and confocal microscopy of PNA sequences were also carried out in vitro on neuroblastoma Kelly cells. Despite the presence of multiple mismatches, the PNA/RNA hetero duplexes retain very interesting features in terms of stability, affinity as well as of cellular uptake.
173 Records (168 escludendo Abstract e Conferenze). Impact factor totale: 662.443 (640.36 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 703.025 (680.789 escludendo Abstract e Conferenze).