IMPDH Inhibitors: Discovery of Antiviral Agents Against Emerging Diseases in .NET framework

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IMPDH Inhibitors: Discovery of Antiviral Agents Against Emerging Diseases
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Department of Pharmaceutical and Biomedical Sciences and The Center for Drug Discovery, The University of Georgia
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INTRODUCTION
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While the discovery and development of various vaccines have provided successful therapeutic approaches to eradicate some serious viral pathogens such as smallpox, polio, measles, mumps, and rubella, there are many existing and emerging viruses that cause serious infectious diseases for which there are no vaccines or therapeutically effective antiviral agents. This is particularly so for some of the RNA viruses that are etiological agents for hemorrhagic fevers. In addition, some viruses, both existing and well-known and others that are emerging, may represent potential weapons of bioterrorism. This chapter presents a brief overview of these viruses and discusses the approach from our laboratory involving rational design, synthesis, and enzymology for the discovery of potential antiviral compounds directed at these viruses.
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SELECTED VIRUSES
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The genus Orthopoxvirus of the Poxviridae family of viruses includes variola, cowpox, vaccinia, and monkeypox viruses, all of which can cause human infections.1 5 The etiologic agent of smallpox is the variola virus. Smallpox has killed tens of millions of people worldwide and, in addition, has dis gured innumerable millions.1 Of the potential biological weapons of bioterrorism, smallpox poses one of the greatest threats,6 8 because in the period between 1977 and 1979, it was
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Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats. Edited by Paul F. Torrence Copyright # 2005 John Wiley & Sons, Inc.
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IMPDH INHIBITORS: DISCOVERY OF ANTIVIRAL AGENTS AGAINST EMERGING DISEASES
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DNA Polymerase Early mRNA RNA Polymerase DNA Packaging Late mRNA
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FIGURE 8.1
Replication cycle of the poxvirus.1
concluded that smallpox had been eradicated worldwide and vaccination programs were discontinued.9 For this reason, a majority of the U.S. population and the world (estimated to be 80%) are vulnerable to smallpox.8 The genome of orthopoxviruses consists of linear, covalently closed, doublestranded DNA of approximately 200 kbp packaged in a large virion.10 Viral DNA and RNA replication occurs in the cytoplasm (Figure 8.1).1 Numerous proteins are present in virions, including a DNA-dependent DNA polymerase, a DNAdependent RNA polymerase, mRNA guanine 7-methyltransferase, mRNA 20 -Omethyltransferase, and DNA topoisomerase. Other poxvirus-encoded enzymes include thymidine kinase and ribonucleotide reductase. The viral mRNAs are capped, polyadenylated at their 30 termini, and not spliced. Poxviruses are more complex in their replication than other DNA viruses and encode more viral enzymes for their replication. DNA replication, which is not fully understood, is directed mainly by viral enzymes and apparently involves a self-priming, strand displacement mechanism in which replicative intermediates serve as templates for the synthesis of genomic DNA.10 Of particular signi cance in the replication of poxviruses is that the DNA of poxviruses encode DNA-dependent RNA polymerases for the synthesis of mRNAs, which subsequently undergo processing called mRNA capping, and then are involved in the synthesis of the many viral proteins of these viruses.10 This viral mRNA processing or capping is essential for viral replication (Figure 8.2).
SELECTED VIRUSES
NH2 N H2N + HOOC-HC-H2CH2C-S CH3 OH N7 -Methyltransferase 2 -O-Methyl transferase O GTP + mRNA Guanyl transferase H2N HN N N N
OH OH
N O OH
S-Adenosylmethionine
O O P O O
O B1 O O O P OH O O P O O OH OH O O B2 O
P O P OCH2 O
O HN H2N N
+ CH3 N N
OH OH
O O P O O
O B1 O O O P O OCH3 O O O P O O O OH B2 O
P O P OCH2
O Capped mRNA
FIGURE 8.2
Chemistry of the capping of viral mRNA.
The family Filoviridae appears to have a single genus, Filovirus, and has two known species, Ebola and Marburg. They cause severe hemorrhagic fever with accompanying high rates of mortality.11,12 The Marburg virus was rst recognized in 1967 and the Ebola virus in 1976. Although loviruses are viewed with much fear and concern in Africa where they have been uncovered, they appear to be largely nonexistent in other parts of the world. However, the potential use of these viruses in warfare or bioterrorism is of very serious concern. There are no drugs available that provide signi cant therapeutic activity against the Marburg or Ebola virus.13
IMPDH INHIBITORS: DISCOVERY OF ANTIVIRAL AGENTS AGAINST EMERGING DISEASES
Attachment Fusion Uncoating
Virus
Budding
Replication/ Transcription
Assembly/Maturation
( ) vRNA Activation/Suppression of Innate Antiviral Response
mRNA
FIGURE 8.3 Replication of loviruses.12
Filoviruses possess a single-stranded, negative-sense RNA genome that is approximately 19 kb.12 The seven viral genes are arranged in a linear mode and the arrangement resembles that of paramyxoviruses. The replication of loviruses (Figure 8.3) has a number of steps that can be targeted by antiviral agents and include, among others, attachment to receptor, fusion, transcription of viral genes, and viral mRNA methylation.12 Two of the steps in the replication cycle of loviruses, viral RNA-dependent RNA polymerase and viral RNA methylation, represent two potential biochemical points of attack in the rationale design of anti lovirus agents. Inhibitors of IMPDH may also provide a possible mechanism for inhibition of lovirus replication (see Section 8.4 for a discussion of inhibitors of IMPDH). In addition to the loviruses, some other RNA viruses that cause viral hemorrhagic fevers include the aviviruses (dengue and yellow fever), arenaviruses (Junin and Lassa), and bunyaviruses (Rift Valley fever and Hantavirus).14 Infectious diseases caused by these viruses result in high mortality because of the lack of availability of therapeutic agents or vaccines. Because many of these viruses are stable and can be delivered by aerosol methods, they may also be considered as potential weapons of bioterrorism.
INOSINE MONOPHOSPHATE DEHYDROGENASE (IMPDH)
The enzyme inosine monophosphate dehydrogenase [IMPDH (EC 1.1.1.205)] catalyzes the conversion of IMP to XMP at the metabolic branch point in the de novo purine nucleotide synthetic pathway (Figure 8.4).15 18 NAD is the coenzyme for this conversion and is reduced to NADH. The enzymatic reaction and its inhibition can be observed by UV spectroscopy through monitoring of the