Novel Peptide Conjugates of Modified Oligonucleotides for Inhibition of Bacterial RNase P

Darya Novopashina; Mariya Vorobyeva; Anton Nazarov; Anna Davydova; Nikolay Danilin; Lyudmila Koroleva; Andrey Matveev; Alevtina Bardasheva; Nina Tikunova; Maxim Kupryushkin; Dmitrii Pyshnyi; Sidney Altman; Alya Venyaminova

doi:10.3389/fphar.2019.00813

Novel Peptide Conjugates of Modified Oligonucleotides for Inhibition of Bacterial RNase P

Front Pharmacol. 2019 Jul 19:10:813. doi: 10.3389/fphar.2019.00813. eCollection 2019.

Authors

Darya Novopashina^{1

2}, Mariya Vorobyeva¹, Anton Nazarov³, Anna Davydova¹, Nikolay Danilin², Lyudmila Koroleva^{1

2}, Andrey Matveev¹, Alevtina Bardasheva¹, Nina Tikunova^{1

2}, Maxim Kupryushkin¹, Dmitrii Pyshnyi^{1

2}, Sidney Altman^{4

5}, Alya Venyaminova¹

Affiliations

¹ Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
² Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia.
³ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
⁴ Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, United States.
⁵ Division of Life Sciences, Arizona State University, Tempe, AZ, United States.

Abstract

Novel alternatives to traditional antibiotics are now of great demand for the successful treatment of microbial infections. Here, we present the engineering and properties of new oligonucleotide inhibitors of RNase P, an essential bacterial enzyme. The series of 2'-O-methyl RNA (2'-OMe-RNA) and phosphoryl guanidine oligonucleotides were targeted to the substrate-binding region of M1 RNA subunit of the RNase P. Uniformly modified 2'-OMe RNA and selectively modified phosphoryl guanidine oligonucleotides possessed good stability in biological media and effectively inhibited RNase P. Their conjugates with transporting peptides were shown to penetrate bacterial cells (Escherichia coli and Acinetobacter baumannii) and inhibit bacterial growth.

Keywords: antibacterial activity; bacterial RNase P; inhibition of RNase P; modified oligonucleotides; oligo(2’-O-methylribonucleotides); penetration into bacterial cells; peptide conjugates of oligonucleotides; phosphoryl guanidine oligonucleotides.