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How do protease inhibitors work?
I've been asked this by family and friends and do not have a clear answer. I know they interupt the replication process but can't seem to find out how. Any help? thanks, jm
HIV has a protein expression stage as well and hence an opportunity for a protease inhibitors to prevent the assembly of new viral particles.There is an additional stage for HIV. The viral genome is RNA and it is copied into DNA by viral enzyme reverse transcriptase. Reverse transcritase inhibitors prevent the process of reverse transcription.
A biochemist friend, explained for me, in "dumb terms" (which i need with this stuff), roughly that the virus replicates by forming a long string that gets chopped up. Protease inhibitors prevent the choping. He went on to explain why Hep C is one of the most difficult viruses to develop a protease inhibitor for (much harder than HIV), so this is cuting edge stuff, but most of it all went over my head from there :-).
From a book I am reading: Killer Cell Dynamics
General life cycle of a virus.
“A virus is basically genetic material wrapped up in a protein coat. It does not have metabolic machinery to reproduce. For reproduction the virus has to enter a cell and use the cell’s metabolic machinery.
The virus attaches to a cell via a receptor and enters the cell. Then, uncoating occurs where the protein coat is lost and the viral genome is exposed. The viral genome is both replicated and expressed (i.e. viral proteins are made). The newly generated viral proteins associate with viral genomes to build new virus particles. The new particles eventually leave the cell.”
As I understand it, Protease inhibitors interfere with the association of the new viral genomes and the new viral proteins.
General life cycle of a virus.
“A virus is basically genetic material wrapped up in a protein coat. It does not have metabolic machinery to reproduce. For reproduction the virus has to enter a cell and use the cell’s metabolic machinery.
The virus attaches to a cell via a receptor and enters the cell. Then, uncoating occurs where the protein coat is lost and the viral genome is exposed. The viral genome is both replicated and expressed (i.e. viral proteins are made). The newly generated viral proteins associate with viral genomes to build new virus particles. The new particles eventually leave the cell.”
As I understand it, Protease inhibitors interfere with the association of the new viral genomes and the new viral proteins.
From Clinical Care Options:
Inhibitors of HCV Posttranslational Processing
Peptidomimetic Inhibitors of NS3/4A Serine Protease
NS3 and NS4A are nonstructural HCV proteins that form a complex that is proteolytically cleaved by a serine protease. This cleavage is required for viral replication and virion assembly. Highly selective, potent peptidomimetic inhibitors of HCV NS3/4A protease have been derived from the viral substrate of the enzyme using structure-based drug design techniques and 2 such agents have now advanced to phase II clinical trials (Table 4).
The first agent, telaprevir (previously known as VX-950), demonstrated activity in a randomized phase Ib study.[31]
The second novel NS3 protease inhibitor in phase II trials is boceprevir (previously known as SCH 503034).
Mike
Inhibitors of HCV Posttranslational Processing
Peptidomimetic Inhibitors of NS3/4A Serine Protease
NS3 and NS4A are nonstructural HCV proteins that form a complex that is proteolytically cleaved by a serine protease. This cleavage is required for viral replication and virion assembly. Highly selective, potent peptidomimetic inhibitors of HCV NS3/4A protease have been derived from the viral substrate of the enzyme using structure-based drug design techniques and 2 such agents have now advanced to phase II clinical trials (Table 4).
The first agent, telaprevir (previously known as VX-950), demonstrated activity in a randomized phase Ib study.[31]
The second novel NS3 protease inhibitor in phase II trials is boceprevir (previously known as SCH 503034).
Mike
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