Design, RNA cleavage and antiviral activity of new artificial ribonucleases derived from mono-, di- and tripeptides connected by linkers of different hydrophobicity

Tamkovich, N. V.; Королева, Л. С.; Kovpak, Mikhail P.; Гончарова, Е. П.; Silnikov, Vladimir N.; Vlassov, Valentin V.; Zenkova, Marina A.

doi:10.1016/j.bmc.2016.02.007

Cited by 8 publications

(2 citation statements)

References 69 publications

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“…Chemical conjugates were first synthesized containing RNA binding and catalytic domains, although their main drawback was their poor catalytic efficiency [8]. Small molecule derived RNases can also be engineered by connecting short mono to tripeptides [279]. The aRNases active site includes imidazole groups and perform an equivalent acid-base catalysis to native enzymes.…”

Section: Other Rnasesmentioning

confidence: 99%

Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses

Boix

2021

Virulence

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Owing to the recent outbreak of Coronavirus Disease of 2019 (COVID-19), it is urgent to develop effective and safe drugs to treat the present pandemic and prevent other viral infections that might come in the future. Proteins from our own innate immune system can serve as ideal sources of novel drug candidates thanks to their safety and immune regulation versatility. Some host defense RNases equipped with antiviral activity have been reported over time. Here, we try to summarize the currently available information on human RNases that can target viral pathogens, with special focus on enveloped single-stranded RNA (ssRNA) viruses. Overall, host RNases can fight viruses by a combined multifaceted strategy, including the enzymatic target of the viral genome, recognition of virus unique patterns, immune modulation, control of stress granule formation, and induction of autophagy/apoptosis pathways. The review also includes a detailed description of representative enveloped ssRNA viruses and their strategies to interact with the host and evade immune recognition. For comparative purposes, we also provide an exhaustive revision of the currently approved or experimental antiviral drugs. Finally, we sum up the current perspectives of drug development to achieve successful eradication of viral infections.

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Section: Other Rnasesmentioning

confidence: 99%

Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses

Boix

2021

Virulence

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“…Efficient RNases should first recognize a specific RNA target, and then provide a proper active site configuration to promote catalysis and ensure the proper cleavage of the substrate. A particular pharmacological interest relies on the design of tailored enzymes with specific RNA cleavage targets (Tamkovich et al, 2016). Recent work on RNases’ action within a cellular environment is helping to unravel their natural in vivo substrates (Honda et al, 2015; Lyons et al, 2017; Mesitov et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Trends in RNA Base Selectivity Within the RNase A Superfamily

Prats-Ejarque

Salazar

et al. 2019

Front. Pharmacol.

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There is a growing interest in the pharmaceutical industry to design novel tailored drugs for RNA targeting. The vertebrate-specific RNase A superfamily is nowadays one of the best characterized family of enzymes and comprises proteins involved in host defense with specific cytotoxic and immune-modulatory properties. We observe within the family a structural variability at the substrate-binding site associated to a diversification of biological properties. In this work, we have analyzed the enzyme specificity at the secondary base binding site. Towards this end, we have performed a kinetic characterization of the canonical RNase types together with a molecular dynamic simulation of selected representative family members. The RNases’ catalytic activity and binding interactions have been compared using UpA, UpG and UpI dinucleotides. Our results highlight an evolutionary trend from lower to higher order vertebrates towards an enhanced discrimination power of selectivity for adenine respect to guanine at the secondary base binding site (B2). Interestingly, the shift from guanine to adenine preference is achieved in all the studied family members by equivalent residues through distinct interaction modes. We can identify specific polar and charged side chains that selectively interact with donor or acceptor purine groups. Overall, we observe selective bidentate polar and electrostatic interactions: Asn to N1/N6 and N6/N7 adenine groups in mammals versus Glu/Asp and Arg to N1/N2, N1/O6 and O6/N7 guanine groups in non-mammals. In addition, kinetic and molecular dynamics comparative results on UpG versus UpI emphasize the main contribution of Glu/Asp interactions to N1/N2 group for guanine selectivity in lower order vertebrates. A close inspection at the B2 binding pocket also highlights the principal contribution of the protein ß6 and L4 loop regions. Significant differences in the orientation and extension of the L4 loop could explain how the same residues can participate in alternative binding modes. The analysis suggests that within the RNase A superfamily an evolution pressure has taken place at the B2 secondary binding site to provide novel substrate-recognition patterns. We are confident that a better knowledge of the enzymes’ nucleotide recognition pattern would contribute to identify their physiological substrate and eventually design applied therapies to modulate their biological functions.

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Design, Synthesis, and Evaluation of Neomycin‐Imidazole Conjugates for RNA Cleavage

et al. 2022

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Targeting RNA with synthetic small molecules attracted much interest during recent years as a particularly promising therapeutic approach in a large number of pathologies spanning from genetic disorders, cancers as well as bacterial and viral infections. In this work, we took advantage of a known RNA binder, neomycin, to prepare neomycin-imidazole conjugates mimicking the active site of ribonuclease enzymes able to induce a site-specific cleavage of HIV-1 TAR RNA in physiological conditions. These new conjugates were prepared using a straightforward synthetic methodology and were studied for their ability to bind the target, inhibit Tat/TAR interaction and induce selective cleavage using fluorescencebased assays and molecular docking. We found compounds with nanomolar affinity, promising cleavage activity and the ability to inhibit Tat/TAR interaction with submicromolar IC 50 s.

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Design, RNA cleavage and antiviral activity of new artificial ribonucleases derived from mono-, di- and tripeptides connected by linkers of different hydrophobicity

Cited by 8 publications

References 69 publications

Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses

Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses

Evolutionary Trends in RNA Base Selectivity Within the RNase A Superfamily

Design, Synthesis, and Evaluation of Neomycin‐Imidazole Conjugates for RNA Cleavage

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