title: Design, RNA cleavage and antiviral activity of new artificial ribonucleases derived from mono-, di- and tripeptides connected by linkers of different hydrophobicity.
abstract: A novel series of metal-free artificial ribonucleases (aRNases) was designed, synthesized and assessed in terms of ribonuclease activity and ability to inactivate influenza virus WSN/A33/H1N1 in vitro. The compounds were built of two short peptide fragments, which include Lys, Ser, Arg, Glu and imidazole residues in various combinations, connected by linkers of different hydrophobicity (1,12-diaminododecane or 4,9-dioxa-1,12-diaminododecane). These compounds efficiently cleaved different RNA substrates under physiological conditions at rates three to five times higher than that of artificial ribonucleases described earlier and displayed RNase A-like cleavage specificity. aRNases with the hydrophobic 1,12-diaminododecane linker displayed ribonuclease activity 3-40 times higher than aRNases with the 4,9-dioxa-1,12-diaminododecane linker. The assumed mechanism of RNA cleavage was typical for natural ribonucleases, that is, general acid-base catalysis via the formation of acid/base pairs by functional groups of amino acids present in the aRNases; the pH profile of cleavage confirmed this mechanism. The most active aRNases under study exhibited high antiviral activity and entirely inactivated influenza virus A/WSN/33/(H1N1) after a short incubation period of viral suspension under physiological conditions.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev Ave, 8, Novosibirsk 630090, Russia.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Tamkovich
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev Ave, 8, Novosibirsk 630090, Russia.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Koroleva
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev Ave, 8, Novosibirsk 630090, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kovpak
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev Ave, 8, Novosibirsk 630090, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Goncharova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev Ave, 8, Novosibirsk 630090, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Silnikov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev Ave, 8, Novosibirsk 630090, Russia.
authors.forename: Valentin
authors.initials: V
authors.lastname: Vlassov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Lavrentiev Ave, 8, Novosibirsk 630090, Russia. Electronic address: marzen@niboch.nsc.ru.
authors.forename: Marina
authors.initials: M
authors.lastname: Zenkova
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009975:Orthomyxoviridae / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry*; D059367:RNA Cleavage / Q000187:drug effects*; D012260:Ribonucleases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D010455:Peptides; D012260:Ribonucleases
keywords: Antiviral activity; Artificial ribonucleases; General acid/base catalysis; Influenza virus; RNA cleavage; Synthesis