Inhibition of hepatitis C virus RNA replicons by peptide aptamers

Alla Trahtenherts; Meital Gal-Tanamy; Romy Zemel; Larisa Bachmatov; Shelly Loewenstein; Ran Tur-Kaspa; Itai Benhar

doi:10.1016/j.antiviral.2007.12.013

Inhibition of hepatitis C virus RNA replicons by peptide aptamers

Alla Trahtenherts, Meital Gal-Tanamy, Romy Zemel, Larisa Bachmatov, Shelly Loewenstein, Ran Tur-Kaspa, Itai Benhar

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Background/aims: Hepatitis C virus infection is a major worldwide health problem, causing chronic hepatitis, cirrhosis and primary liver cancer. In addition to its role in the viral polyprotein-processing, the viral NS3 serine protease has been implicated in interactions with various cell constituents resulting in phenotypic changes including malignant transformation. NS3 is currently regarded a prime target for anti-viral drugs thus specific inhibitors of its activities should be important. With the aim of inhibiting NS3 protease activity as a means to inhibit HCV replication we used a novel bacterial genetic screen to isolate NS3-inhibiting peptide aptamers. Methods: We have isolated and characterized seven NS3-inhibiting peptide aptamers. We investigated the phenotypic changes that SEAP-secreting subgenomic RNA replicons undergo upon intracellular expression of these peptide aptamers, assayed by real-time RT-PCR and inhibition of SEAP secretion by transfected replicon cells. Results and conclusions: The peptide aptamers inhibited NS3 protease activity in vitro with an IC₅₀ in the low micromolar range. Upon transfection, aptamers inhibited the replication of SEAP-secreting genotype 1b subgenomic RNA replicons. Aptamer-based intracellular immunization may emerge as a promising antiviral approach to interfere with the life cycle and pathogenicity of HCV.

Original language	English
Pages (from-to)	195-205
Number of pages	11
Journal	Antiviral Research
Volume	77
Issue number	3
DOIs	https://doi.org/10.1016/j.antiviral.2007.12.013
State	Published - Mar 2008
Externally published	Yes

Bibliographical note

Funding Information:
We thank Prof. Matti Sällberg (Karolinska Institutet, Stockholm, Sweden) for the 1a genotype-coding plasmid. We thank Prof. Stanley Lemon (The University of Texas Medical Branch, Galveston, Texas, USA) for the 1b genotype SEAP-secreting RNA replicons. This work was supported by a research grants from the Horowitz Fund, Israel and the Israel Cancer Association.

Keywords

HCV
Liver diseases
NS3 serine protease
Peptide aptamers
RNA replicons

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.antiviral.2007.12.013

Cite this

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title = "Inhibition of hepatitis C virus RNA replicons by peptide aptamers",

abstract = "Background/aims: Hepatitis C virus infection is a major worldwide health problem, causing chronic hepatitis, cirrhosis and primary liver cancer. In addition to its role in the viral polyprotein-processing, the viral NS3 serine protease has been implicated in interactions with various cell constituents resulting in phenotypic changes including malignant transformation. NS3 is currently regarded a prime target for anti-viral drugs thus specific inhibitors of its activities should be important. With the aim of inhibiting NS3 protease activity as a means to inhibit HCV replication we used a novel bacterial genetic screen to isolate NS3-inhibiting peptide aptamers. Methods: We have isolated and characterized seven NS3-inhibiting peptide aptamers. We investigated the phenotypic changes that SEAP-secreting subgenomic RNA replicons undergo upon intracellular expression of these peptide aptamers, assayed by real-time RT-PCR and inhibition of SEAP secretion by transfected replicon cells. Results and conclusions: The peptide aptamers inhibited NS3 protease activity in vitro with an IC50 in the low micromolar range. Upon transfection, aptamers inhibited the replication of SEAP-secreting genotype 1b subgenomic RNA replicons. Aptamer-based intracellular immunization may emerge as a promising antiviral approach to interfere with the life cycle and pathogenicity of HCV.",

keywords = "HCV, Liver diseases, NS3 serine protease, Peptide aptamers, RNA replicons",

author = "Alla Trahtenherts and Meital Gal-Tanamy and Romy Zemel and Larisa Bachmatov and Shelly Loewenstein and Ran Tur-Kaspa and Itai Benhar",

note = "Funding Information: We thank Prof. Matti S{\"a}llberg (Karolinska Institutet, Stockholm, Sweden) for the 1a genotype-coding plasmid. We thank Prof. Stanley Lemon (The University of Texas Medical Branch, Galveston, Texas, USA) for the 1b genotype SEAP-secreting RNA replicons. This work was supported by a research grants from the Horowitz Fund, Israel and the Israel Cancer Association.",

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AU - Trahtenherts, Alla

AU - Gal-Tanamy, Meital

AU - Zemel, Romy

AU - Bachmatov, Larisa

AU - Loewenstein, Shelly

AU - Tur-Kaspa, Ran

AU - Benhar, Itai

N1 - Funding Information: We thank Prof. Matti Sällberg (Karolinska Institutet, Stockholm, Sweden) for the 1a genotype-coding plasmid. We thank Prof. Stanley Lemon (The University of Texas Medical Branch, Galveston, Texas, USA) for the 1b genotype SEAP-secreting RNA replicons. This work was supported by a research grants from the Horowitz Fund, Israel and the Israel Cancer Association.

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N2 - Background/aims: Hepatitis C virus infection is a major worldwide health problem, causing chronic hepatitis, cirrhosis and primary liver cancer. In addition to its role in the viral polyprotein-processing, the viral NS3 serine protease has been implicated in interactions with various cell constituents resulting in phenotypic changes including malignant transformation. NS3 is currently regarded a prime target for anti-viral drugs thus specific inhibitors of its activities should be important. With the aim of inhibiting NS3 protease activity as a means to inhibit HCV replication we used a novel bacterial genetic screen to isolate NS3-inhibiting peptide aptamers. Methods: We have isolated and characterized seven NS3-inhibiting peptide aptamers. We investigated the phenotypic changes that SEAP-secreting subgenomic RNA replicons undergo upon intracellular expression of these peptide aptamers, assayed by real-time RT-PCR and inhibition of SEAP secretion by transfected replicon cells. Results and conclusions: The peptide aptamers inhibited NS3 protease activity in vitro with an IC50 in the low micromolar range. Upon transfection, aptamers inhibited the replication of SEAP-secreting genotype 1b subgenomic RNA replicons. Aptamer-based intracellular immunization may emerge as a promising antiviral approach to interfere with the life cycle and pathogenicity of HCV.

AB - Background/aims: Hepatitis C virus infection is a major worldwide health problem, causing chronic hepatitis, cirrhosis and primary liver cancer. In addition to its role in the viral polyprotein-processing, the viral NS3 serine protease has been implicated in interactions with various cell constituents resulting in phenotypic changes including malignant transformation. NS3 is currently regarded a prime target for anti-viral drugs thus specific inhibitors of its activities should be important. With the aim of inhibiting NS3 protease activity as a means to inhibit HCV replication we used a novel bacterial genetic screen to isolate NS3-inhibiting peptide aptamers. Methods: We have isolated and characterized seven NS3-inhibiting peptide aptamers. We investigated the phenotypic changes that SEAP-secreting subgenomic RNA replicons undergo upon intracellular expression of these peptide aptamers, assayed by real-time RT-PCR and inhibition of SEAP secretion by transfected replicon cells. Results and conclusions: The peptide aptamers inhibited NS3 protease activity in vitro with an IC50 in the low micromolar range. Upon transfection, aptamers inhibited the replication of SEAP-secreting genotype 1b subgenomic RNA replicons. Aptamer-based intracellular immunization may emerge as a promising antiviral approach to interfere with the life cycle and pathogenicity of HCV.

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Inhibition of hepatitis C virus RNA replicons by peptide aptamers

Abstract

Bibliographical note

Keywords

UN SDGs

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