Exploring the Role of Antiviral Drugs in the Eradication of Polio Workshop Report (2006) / Chapter Skim
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3 Potential Biological Targets for Polio Antiviral Drugs
3 Potential Biological Targets for Polio Antiviral Drugs
Pages 19-34
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From page 19... ...
A consensus sequence can be defined for the poliovirus genome, but an infection will actually consist of thousands of genomes, each differing slightly from the consensus. The reason for this phenomenon, which has profound biological consequences, is a high inherent error rate (about 1 nucleotide of every 10,000 is misincorporated during genome replication)
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From page 20... ...
with the receptor CD155, of polyprotein synthesis and processing, and genome replication will be pro
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From page 21... ...
Individual steps of the replication cycle at the cellular level have been studied in great detail, which will aid in the identification of targets for poliovirus antiviral drugs. Currently, the forerunners are small molecules that interfere with the entry of the virion into the host cell (drugs that insert themselves into the capsid)
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From page 22... ...
22 ROLE OF ANTIVIRAL DRUGS IN THE ERADICATION OF POLIO FIGURE 1 Schematic representation of the cellular replication cycle of poliovirus.
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From page 23... ...
The lack of detailed understanding of the sites of poliovirus replication may be an obstacle to drug development in that those sites cannot currently be specifically targeted for monitoring drug activity.
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From page 24... ...
. If the natural pocket factor is replaced by hydrophobic compounds that lodge more stably in the pocket (for example, binding of the WIN51711 compound into the poliovirus pocket)
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From page 25... ...
. Since cross-over occurs predominantly near the middle of the genomes, the cVDPV recombinants, which have acquired coding sequences of nonstructural proteins of C-CAVs, may be resistant to drugs directed at the poliovirus encoded enzymes (e.g., proteinases or RNA polymerase)
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From page 26... ...
Proteinases 3C/3CDpro The relatively stable processing intermediate 3CDpro is not only a proteinase but also an RNA-binding protein essential for genome replication. Once cleaved, 3CDproyields the smaller proteinase 3Cpro and the viral RNA polymerase 3Dpol.
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From page 27... ...
27 pol 3D 3D n A NTR A A 3' pro P3 * D 3C 3CD pro 3C 3D 3C P3 Region *
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From page 28... ...
. 3CDpro is also a cofactor in the formation of a ribonucleoprotein complex between the RNA polymerase 3Dpol, a small viral protein VPg, and a cis-acting replication element (cre stem loop)
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From page 29... ...
2. Inhibitors of the Poliovirus RNA-Dependent RNA Polymerase 3Dpol Poliovirus genome replication follows a common strategy used by all single-stranded plus-strand RNA viruses; the plus-stranded genomic RNA is transcribed into minus-strand copies, which then serve as templates for progeny genomic RNA (Wimmer et al.
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From page 30... ...
Nucleoside analogues with mutagenic potential, such as ribavirin, have been identified, but additional work is necessary to establish whether they are effective antipoliovirus drugs. It is recommended that screening of libraries be undertaken to identify nonnucleoside compounds that inhibit polymerase function both by interfering with replication and by altering the mutation rate of poliovirus.
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From page 31... ...
, take advantage of the RNA polymerases' high error rate to induce the virus to incorporate faulty nucleosides as it replicates. One way that viruses acquire resistance to nucleoside-based mutagens is by having mutations that improve the fidelity of their RNA polymerases.
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From page 32... ...
If the current problems with delivery in humans were resolved, siRNA might be a viable alternative for prophylaxis of and therapy for poliovirus infections. Morpholinos Morpholinos are similar to siRNAs in that they are short strands of nucleic acid designed to bind to specific complementary stretches on target RNA (Arora et al.
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From page 33... ...
The close genetic and biochemical kinship of human enteroviruses and rhinoviruses suggests that compounds developed previously against these picornaviruses might serve as superb immediate candidates for the development of antipoliovirus agents. In spite of a wealth of information related to intracellular poliovirus replication, the details of individual steps (such as uptake of virus into the cell, regulation of polyprotein processing, the switch from translation to genome synthesis, regulation of plus-strand and minus-strand synthesis, rearrangement of cellular organelles, and encapsidation and virus maturation)
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