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Capsid-Targeted Viral Inactivation: A Novel Tactic for Inhibiting Replication in Viral Infections

View Article: PubMed Central - PubMed

ABSTRACT

Capsid-targeted viral inactivation (CTVI), a conceptually powerful new antiviral strategy, is attracting increasing attention from researchers. Specifically, this strategy is based on fusion between the capsid protein of a virus and a crucial effector molecule, such as a nuclease (e.g., staphylococcal nuclease, Barrase, RNase HI), lipase, protease, or single-chain antibody (scAb). In general, capsid proteins have a major role in viral integration and assembly, and the effector molecule used in CTVI functions to degrade viral DNA/RNA or interfere with proper folding of viral key proteins, thereby affecting the infectivity of progeny viruses. Interestingly, such a capsid–enzyme fusion protein is incorporated into virions during packaging. CTVI is more efficient compared to other antiviral methods, and this approach is promising for antiviral prophylaxis and therapy. This review summarizes the mechanism and utility of CTVI and provides some successful applications of this strategy, with the ultimate goal of widely implementing CTVI in antiviral research.

No MeSH data available.


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The main mechanism of capsid-targeted viral inactivation (CTVI). (A) Comparison of viral genome encapsidation in a normal virus and a virus containing a capsid–enzyme fusion protein [3]. a. Normal assembly of viruses, whereby nucleic acid is enveloped by capsid proteins to form the nucleocapsid; b. The assembly process of the virus with a fusion protein composed of a capsid protein and a degradative enzyme (e.g., staphylococcal nuclease (SN)) that is calcium ion (Ca2+) dependent. The fusion protein is incorporated into the internal virion during viral assembly, where is has direct access to nucleic acid. When the Ca2+ concentration reaches the millimolar range, the enzyme is activated and digests the viral RNA/DNA; (B) A schematic representation of the CTVI mechanism. Infection of a cell by a virus stably expressing a fusion protein mainly includes the following steps: a. The virus enters the host cell through the endocytosis pathway; b. the fusion protein is stably expressed; c. using material supplied by the host cell, the fusion protein is incorporated into the viral structure during viral assembly; d. the virus is assembled and modified to form a mature virion within closed vesicles in the cytoplasm, but the nuclease in the virion is inactive due to the intracellular nanomolar Ca2+ concentration; e. the virus is released into the extracellular environment; f. the nuclease incorporated into the progeny virion is active in the extracellular millimolar Ca2+ concentration, where it can degrade the viral nucleic acids.
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viruses-08-00258-f001: The main mechanism of capsid-targeted viral inactivation (CTVI). (A) Comparison of viral genome encapsidation in a normal virus and a virus containing a capsid–enzyme fusion protein [3]. a. Normal assembly of viruses, whereby nucleic acid is enveloped by capsid proteins to form the nucleocapsid; b. The assembly process of the virus with a fusion protein composed of a capsid protein and a degradative enzyme (e.g., staphylococcal nuclease (SN)) that is calcium ion (Ca2+) dependent. The fusion protein is incorporated into the internal virion during viral assembly, where is has direct access to nucleic acid. When the Ca2+ concentration reaches the millimolar range, the enzyme is activated and digests the viral RNA/DNA; (B) A schematic representation of the CTVI mechanism. Infection of a cell by a virus stably expressing a fusion protein mainly includes the following steps: a. The virus enters the host cell through the endocytosis pathway; b. the fusion protein is stably expressed; c. using material supplied by the host cell, the fusion protein is incorporated into the viral structure during viral assembly; d. the virus is assembled and modified to form a mature virion within closed vesicles in the cytoplasm, but the nuclease in the virion is inactive due to the intracellular nanomolar Ca2+ concentration; e. the virus is released into the extracellular environment; f. the nuclease incorporated into the progeny virion is active in the extracellular millimolar Ca2+ concentration, where it can degrade the viral nucleic acids.

Mentions: The strategy proposed by Natsoulis and Boeke [3] in 1991 was first used in a model of yeast retrotransposon Ty1, and the method has since been applied to various viruses. The mechanism underlying this strategy is based on the fact that viral DNA or RNA is encapsidated into a protein shell, forming a complex. The complex, comprising capsid proteins and nucleic acid, is termed the nucleocapsid (Figure 1Aa). As the protein of the nucleocapsid participates in viral assembly, a fusion protein consisting of a virus nucleocapsid protein and a foreign protein (an effector such as a nuclease [26,27], lipase, protease, or single-chain antibody (scAb) [12,20,28] is generated. The fusion protein is then incorporated into the virus particle. Therefore, the effector molecule of the fusion protein has direct access to the nucleic acid or protein components of viruses. In particular (Figure 1Ab), the fusion protein can degrade DNA/RNA [29,30] or disrupt the protein composition of the virus [21], resulting in an antiviral effect.


Capsid-Targeted Viral Inactivation: A Novel Tactic for Inhibiting Replication in Viral Infections
The main mechanism of capsid-targeted viral inactivation (CTVI). (A) Comparison of viral genome encapsidation in a normal virus and a virus containing a capsid–enzyme fusion protein [3]. a. Normal assembly of viruses, whereby nucleic acid is enveloped by capsid proteins to form the nucleocapsid; b. The assembly process of the virus with a fusion protein composed of a capsid protein and a degradative enzyme (e.g., staphylococcal nuclease (SN)) that is calcium ion (Ca2+) dependent. The fusion protein is incorporated into the internal virion during viral assembly, where is has direct access to nucleic acid. When the Ca2+ concentration reaches the millimolar range, the enzyme is activated and digests the viral RNA/DNA; (B) A schematic representation of the CTVI mechanism. Infection of a cell by a virus stably expressing a fusion protein mainly includes the following steps: a. The virus enters the host cell through the endocytosis pathway; b. the fusion protein is stably expressed; c. using material supplied by the host cell, the fusion protein is incorporated into the viral structure during viral assembly; d. the virus is assembled and modified to form a mature virion within closed vesicles in the cytoplasm, but the nuclease in the virion is inactive due to the intracellular nanomolar Ca2+ concentration; e. the virus is released into the extracellular environment; f. the nuclease incorporated into the progeny virion is active in the extracellular millimolar Ca2+ concentration, where it can degrade the viral nucleic acids.
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viruses-08-00258-f001: The main mechanism of capsid-targeted viral inactivation (CTVI). (A) Comparison of viral genome encapsidation in a normal virus and a virus containing a capsid–enzyme fusion protein [3]. a. Normal assembly of viruses, whereby nucleic acid is enveloped by capsid proteins to form the nucleocapsid; b. The assembly process of the virus with a fusion protein composed of a capsid protein and a degradative enzyme (e.g., staphylococcal nuclease (SN)) that is calcium ion (Ca2+) dependent. The fusion protein is incorporated into the internal virion during viral assembly, where is has direct access to nucleic acid. When the Ca2+ concentration reaches the millimolar range, the enzyme is activated and digests the viral RNA/DNA; (B) A schematic representation of the CTVI mechanism. Infection of a cell by a virus stably expressing a fusion protein mainly includes the following steps: a. The virus enters the host cell through the endocytosis pathway; b. the fusion protein is stably expressed; c. using material supplied by the host cell, the fusion protein is incorporated into the viral structure during viral assembly; d. the virus is assembled and modified to form a mature virion within closed vesicles in the cytoplasm, but the nuclease in the virion is inactive due to the intracellular nanomolar Ca2+ concentration; e. the virus is released into the extracellular environment; f. the nuclease incorporated into the progeny virion is active in the extracellular millimolar Ca2+ concentration, where it can degrade the viral nucleic acids.
Mentions: The strategy proposed by Natsoulis and Boeke [3] in 1991 was first used in a model of yeast retrotransposon Ty1, and the method has since been applied to various viruses. The mechanism underlying this strategy is based on the fact that viral DNA or RNA is encapsidated into a protein shell, forming a complex. The complex, comprising capsid proteins and nucleic acid, is termed the nucleocapsid (Figure 1Aa). As the protein of the nucleocapsid participates in viral assembly, a fusion protein consisting of a virus nucleocapsid protein and a foreign protein (an effector such as a nuclease [26,27], lipase, protease, or single-chain antibody (scAb) [12,20,28] is generated. The fusion protein is then incorporated into the virus particle. Therefore, the effector molecule of the fusion protein has direct access to the nucleic acid or protein components of viruses. In particular (Figure 1Ab), the fusion protein can degrade DNA/RNA [29,30] or disrupt the protein composition of the virus [21], resulting in an antiviral effect.

View Article: PubMed Central - PubMed

ABSTRACT

Capsid-targeted viral inactivation (CTVI), a conceptually powerful new antiviral strategy, is attracting increasing attention from researchers. Specifically, this strategy is based on fusion between the capsid protein of a virus and a crucial effector molecule, such as a nuclease (e.g., staphylococcal nuclease, Barrase, RNase HI), lipase, protease, or single-chain antibody (scAb). In general, capsid proteins have a major role in viral integration and assembly, and the effector molecule used in CTVI functions to degrade viral DNA/RNA or interfere with proper folding of viral key proteins, thereby affecting the infectivity of progeny viruses. Interestingly, such a capsid–enzyme fusion protein is incorporated into virions during packaging. CTVI is more efficient compared to other antiviral methods, and this approach is promising for antiviral prophylaxis and therapy. This review summarizes the mechanism and utility of CTVI and provides some successful applications of this strategy, with the ultimate goal of widely implementing CTVI in antiviral research.

No MeSH data available.


Related in: MedlinePlus