Poster Presenter
Design, Synthesis and Anti-Influenza Activity of Artificial
Ribonucleases
Koroleva L.S., Burakova E.A., Lozitsky V.P.,
Fedchuk A.S., Silnikov V.N.
Russia
The synthesis of molecules that are capable of nonrandom RNA
cleavage has found a variety of important applications. Such molecules
are used in rational design of novel antiviral, since RNA is the genetic
material of many pathogenic viruses. We have designed and synthesized
artificial ribonucleases (artRNases) based on short peptides mimicking
of RNAse T1 catalytic center. Ability of artificial RNases to RNA
cleavage was shown in experiments with 96-mer RNA HIV-1. Anti-influenza
activity in vitro of 15 such artRNases was investigated by
inhibition of reproduction virus A/Hong Kong/1/68 (H3N2) in tissue
cultures of chorioallantoic membranes (CCM) of 12-14 days age chick
embryos. Samples of compounds under examination were dissolved in
special medium to 10-3 M concentration. CCM were infected with 1000
TID50 (tissue infection dose) of influenza virus. Studied synthetic
RNases were divided on 4 groups: 1) - tetrapeptides bearing lipophobic
fragment; 2) - polycationic structures containing an aromatic framework
with two residues of bis-quaternary salts of 1,4-diazabicyclo[2.2.2]octane
(Dp12, Dm4, D5-12); 3) - peptide-like molecules containing hydrophilic
linker within molecule (K-L1-K, S-L1-S, R-L1-R, pep1-L1-pep1, pep2-L1-pep2,
pep3-L1-pep3); 4) - peptide-like molecules containing hydrophobic
linker within molecule (E-L2-E, K-L2-K, S-L2-S and EBzl-L2-EBzl).
In 1st group compound EGKG-OAlk decreased virus amount on 1.0 log10
TID50. In 2nd group compound D5-12 inhibited replication of influenza
virus on 5,4 log10 TID50. In 3rd group peptides pep1-L1-pep1, S-L1-S
and R-L1-R exhibited antiviral activity from 1,75 to till 2.75 log10
TID50 and compounds K-L1-K and pep3-L1-pep3 decreased virus amount
on 3.9 and 4.3 log10 TID50 respectively. In 4th group compounds E-L2-E
and K-L2-K inhibited replication of influenza virus from 2.0 till
3.04 log10 TID50. Antiviral activity of compounds EBzl-L2-EBzl and
S-L2-S was more than 5.0 log10 TID50.
The research is supported by integration grant #88 from Siberian Branch
of Russian Academy of Sciences and RFBR grants #09-04-01483, 07-04-00990-a,
08-04-90038-Bel_a
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