RNase H-sensitive multifunctional ASO-based constructs as promising tools for the treatment of multifactorial complex pathologies

• Published in: Bioorganic chemistry 2024-09, Vol.150, p.107595, Article 107595
• Main Authors: Mata-Ventosa, Aida, Vila-Planas, Ariadna, Solsona-Pujol, Aina, Dueña, Jordi de la, Torrents, Maria, Izquierdo-García, Eduardo, Pastor-Anglada, Marçal, Pérez-Torras, Sandra, Terrazas, Montserrat
• Format: Article
• Language: English
• Subjects: 3ASO multitargeting tool; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antisense oligonucleotides; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Complex pathologies; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Escherichia coli - drug effects; Humans; Molecular Structure; Oligonucleotides, Antisense - chemistry; Oligonucleotides, Antisense - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Ribonuclease H - antagonists & inhibitors; Ribonuclease H - metabolism; RNase H; Stimuli-responsive; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107595

[Display omitted] •Unprecedented RNase H-sensitive RNA·DNA PS-based multitargeting oligonucleotide nanostructure.•Multifunctional ASO-based structure dictates an undescribed mode of RNase H cleavage.•Simultaneous release of three different therapeutic oligonucleotides (ASOs).•Proof of concept to overcome cooperative cross-activation inhibiting three oncogenes. Combined therapies play a key role in the fight against complex pathologies, such as cancer and related drug-resistance issues. This is particularly relevant in targeted therapies where inhibition of the drug target can be overcome by cross-activating complementary pathways. Unfortunately, the drug combinations approved to date –mostly based on small molecules– face several problems such as toxicity effects, which limit their clinical use. To address these issues, we have designed a new class of RNase H-sensitive construct (3ASO) that can be disassembled intracellularly upon cell entry, leading to the simultaneous release of three different therapeutic oligonucleotides (ONs), tackling each of them the mRNA of a different protein. Here, we used Escherichia coli RNase H1 as a model to study an unprecedented mode of recognition and cleavage, that is mainly dictated by the topology of our RNA·DNA-based hybrid construct. As a model system for our technology we have created 3ASO constructs designed to specifically inhibit the expression of HER2, Akt and Hsp27 in HER2+ breast cancer cells. These trifunctional ON tools displayed very low toxicity and good levels of antiproliferative activity in HER2+ breast cancer cells. The present study will be of great potential in the fight against complex pathologies involving multiple mRNA targets, as the proposed cleavable designs will allow the efficient single-dose administration of different ON drugs simultaneously.