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Targeting specific RNAs by antisense oligonucleotides - ASOs

Inhibition of bacterail growth by targeting specific RNAs by ASOs.

Figure 1. (A) Binding of RNAP to the promoter site of the genomic DNA (1) triggers transcription of polycistronic mRNA containing genes A, B and C (2). Antisense oligonucleotides can transfer into the cell (3) and bind with complementary sequences of the mRNA (4). The binding of ASO leads to the formation of a doublestranded molecule, which is recognized by RNase H (5). Binding of RNase H triggers cleavage of the mRNA (6). With mRNA being cleaved, there is non-protein expression (7). RNase P (9) can also recognize the double-stranded molecule formed by the binding of ASO with the mRNA (8). Binding of RNase P triggers cleavage of mRNA (10), leading to non-protein expression. (B) Binding of RNAP to the promoter site of genomic DNA (1) triggers transcription of mRNA containing genes 1, 2 and 3 (2). PNA, an antisense oligonucleotide, can transfer into the cell (3) and bind with complementary sequences of the mRNA (4). PNA leads to prevention of ribosomal subunits binding to mRNA (5), leading to no translation (6). In the absence of ASOs, ribosomal subunits bind and mRNA are translated into a functional protein (7). Entering of a small drug molecule into the cell (8), as it binds to its target, which is the functional protein (9), leads to protein function inhibition (10).

In recent years, various ASO technologies have been developed for applications in different organisms including bacteria. In fact, the concept of using antisense antibiotics does not look as revolutionary and impractical as a decade ago. Having experienced certain vicissitudes in the past decade, we are now on the threshold of developing and utilizing various ASO technologies, including antisense antibiotics. This is because in the last several years, significant technology advances were achieved in the fields of genomics, structural modification of oligonucleotides and efficient delivery system. These advances have led to fundamental progress in the prospective of developing antisense antibiotics. They include all three main areas that had hampered the development of antisense antibiotics in the past, namely, target validation, efficiency and specificity of ASO inhibition and ASO delivery in vivo.

References:

1. Martina Traykovska, Katya B. Popova and Robert Penchovsky - Targeting glmS ribozyme with chimeric antisense oligonucleotides for antibacterial drug development, ACS Synthetic Biology (2021), IF:5.5 (Q1, Scopus)

2. Robert Penchovsky, Stoilova C.C. - Riboswitch-based antibacterial drug discovery using high-throughput screening methods – 2013, Expert Opinion on Drug Discovery, 1746-0441, Q1 (Pharmacology, Toxicology and Pharmaceutics) , IF – 4,676

3. Robert Penchovsky and Martina Traykovska - Designing drugs that overcome antibacterial resistance: where do we stand and what should we do? – 2015, Expert opinion on drug discovery, Q1 (Pharmacology, Toxicology and Pharmaceutics), IF – 4,66

4. Aikaterini Valsamatzi-PanagiotouKatya B. Popova and Robert Penchovsky - Chapter 9: Drug Discovery for Targeting Drug Resistant Bacteria – 2020, Sustainable Agriculture Reviews 46, Mitigation of Antimicrobial Resistance Vol. 1, Tools and Targets:.

5. Aikaterini Valsamatzi-PanagiotouKatya B. Popova and Robert Penchovsky - Chapter 1: Strategies for prevention and containment of antimicrobial resistance – 2020, Sustainable Agriculture Reviews 49 Mitigation of Antimicrobial Resistance Vol. 2, Natural and Synthetic Approaches.

6. Aikaterini Valsamatzi-Panagiotou and Robert Penchovsky - Archieves of Clinical Microbiology - Engineering antisense oligonucleotides as antibacterial agents(2019)…IF:1.05.

7. Martina Traykovska, Katya B. Popova and Robert Penchovsky - Targeting glmS Ribozyme with Chimeric Antisense Oligonucleotides for Antibacterial Drug Development - ACS Synthetic Biology (2021)…, Q1 (Pharmacology, Toxicology and Pharmaceutics), IF – 5,5

8. Martina Traykovska and Robert Penchovsky - Engineering antisense oligonucleotides as antibacterial agents that target FMN riboswitches and inhibit the growth of Staphylococcus aureus, Listeria monocytogenes, and Escherichia coli - ACS Synthetic Biology (2022)…, Q1 (Pharmacology, Toxicology and Pharmaceutics), IF – 5,5