MPA EICAR Tiazofurin Pyrazofurin 6-Azauridine CPE-C Arenaviridae 110 in .NET

Creator QR Code ISO/IEC18004 in .NET MPA EICAR Tiazofurin Pyrazofurin 6-Azauridine CPE-C Arenaviridae 110
38 MPA EICAR Tiazofurin Pyrazofurin 6-Azauridine CPE-C Arenaviridae 110
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TABLE 3.5
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In Vitro Antiviral Activity of Inhibitors of IMPDH, OMP Decarboxylase, CTP Synthetase, and SAH Hydrolase C3-NPC A C-c3Ado
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Genus
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Virus
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Arenavirus
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Lymphocytic choriomeningitis Lassa Junin Pichinde Tacaribe 64 59 Bunyaviridae 110 59 110 59
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59,82 59,82
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59 59
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Bunyavirus Hantavirus Nairovirus Phlebovirus 86 86 64 72 67 64 79 Filoviridae
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La Crosse Hantaan CCHFV Rift Valley fever Sand y fever Punta Toro
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110
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72 77 78
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111
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Filovirus
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Ebola
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117,118
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Togaviridae 81 Flaviviridae
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86,87
Alphavirus 81 84 82
VEE Semliki Forest
110
Flavivirus
86 64,67 86,110
Japanese encephalitis Yellow fever Dengue West Nile 87 47 47 Poxviridae
64,67,86,119 119
85 85,86 85 47,85 111 86 47,120 86 47
Orthopoxvirus 49 49 49 49 81 122 49 49 49 49
Variola Vaccinia Cowpox Monkeypox Camelpox
81,92,122 92 92
121 82,121,122 121 121
92 92,122 124 92 92
92 92,122 92 92
Activity: , active; , moderate; , inactive.
OVERVIEW OF ANTIVIRAL DRUG DISCOVERY AND DEVELOPMENT
Nevertheless, the Working Group on Civilian Biodefense has recommended similar doses of ribavirin to treat patients with clinically evident viral hemorrhagic fever of unknown etiology or secondary to arenaviruses or bunyaviruses.96 3.2.2 IMPDH Inhibitors
IMPDH catalyzes the conversion of IMP to XMP, an essential step in the de novo biosynthesis of guanine nucleotides. Inhibition results in lowing intracellular GTP and dGTP pools. Other than ribavirin (a competitive inhibitor), known inhibitors include mycophenolic acid 2 (MPA; an uncompetitive inhibitor), tiazofurin 3, and EICAR 4. Their in vitro antiviral activity is summarized in Table 3.5. It was found
O O O OCH3 CH3 2 OH OH 3 O N HO N O NH2 C CH OH CH3 OH O HO S O N NH2
OH OH 4
that the order and potency of anti-YFV activity of compounds correlates with the activity of the compounds against the enzyme: MPA > EICAR > tiazofurin > ribavirin.86 MPA is also an immunosuppressant due to its ability to reduce both T and B lymphocyte proliferation via inhibition of IMPDH.43,108 Combinations of ribavirin and tiazofurin showed synergistic effects in vitro against YFV and JEV but showed additive effects against Korean hemorrhagic fever virus and RVFV.67 VX-497 5 is a new reversible uncompetitive IMPDH inhibitor. Its range of activity includes VEEV.109
CH3 O O N 5 H N O H N O O N H O
BROAD-SPECTRUM ANTIVIRAL AGENTS
OMP Decarboxylase Inhibitors
This enzyme controls the conversion of OMP to UMP in de novo pyrimidine biosynthesis. Prototypic inhibitors are pyrazofurin 6 and 6-azauridine 7. Their in vitro activity is summarized in Table 3.5. Despite this activity, pyrazofurin failed to show ef cacy against Pichinde virus and VEE in mice and guinea pigs.110
O NH2 OH O N HO O N O NH O
H N N HO
OH OH 6
OH OH 7
CTP Synthetase Inhibitors
This enzyme catalyzes the conversion of UTP to CTP in the last step of de novo pyrimidine biosynthesis. Cyclopentenylcytosine 8 (CPE-C) is a well-known inhibitor of this enzyme.82, 111 Its in vitro antiviral activity is summarized in Table 3.5.
NH2 N N HO O
OH OH 8
SAH Hydrolase Inhibitors
SAH hydrolase is an intracellular enzyme that regulates biological transmethylation in general. Since many animal viruses require SAH hydrolase in the methylation of the 50 -terminal residue of viral mRNA for forming the cap structure necessary for viral protein translation and replication, this enzyme has been recognized as a suitable antiviral target.112 116 3-Deazaneplanocin A 9 (c3-NPC A) and carbocyclic 3-deazaadenosine 10 (C-c3Ado) are two representative inhibitors. Their in vitro activity is summarized in Table 3.5. SAH inhibitors are inactive against togaviruses and aviviruses.11 However, they have demonstrated potent activity against Ebola virus in cell cultures and in mice (see Section 3.9).
OVERVIEW OF ANTIVIRAL DRUG DISCOVERY AND DEVELOPMENT
NH2 N N HO N HO N N
NH2 N
OH OH 9
OH OH 10
Immunomodulators
The antiviral effect elicited by immunomodulators can only be assessed in animal models. 7-Thia-8-oxoguanosine 11 was effective both prophylactically and therapeutically against SFV and Punta Toro virus (PTV) in mice.79,125 127 7-Deazaguanosine 12 and 8-chloro-7-deazaguanosine 13 were orally active against SFV in mice.128 130 IFN induction appears to be the reason for their antiviral activity.
O S O HO N O N NH NH2 HO N O N O NH NH2
OH OH 11 O Cl HO N O N NH
OH OH 12
OH OH 13
INHIBITORS OF ORTHOPOXVIRUSES
Variola virus (the causative agent of smallpox) is presumably one of the most attractive pathogens to a potential bioterrorist, as it meets the twin criteria of high transmissibility and high mortality. In addition, survivors are left with dis guring sequelae. Historically, drugs were tried both for treatment of smallpox and for prophylaxis of contacts but rarely in well-controlled clinical trials. Postexposure
INHIBITORS OF ORTHOPOXVIRUSES
CH3 N O N S 14
NH NH2
prophylaxis with marboran (N-methylisatin b-thiosemicarbazone) 14 was hailed as the most signi cant advance in smallpox control since the days of Jenner. 131 Yet this in uential study was seriously awed by current standards as most subjects were successfully vaccinated in infancy and revaccinated before receiving therapy. In addition, the study groups were not randomized and subject compliance with the dosing schedule was not adequately ascertained.132 Historical data on complication rates from the past will probably not be reliable predictors of future rates should any government undertake the vaccination of large segments of the population to deter or ameliorate the consequences of a potential terrorist use of smallpox. The world s population has changed dramatically since the middle of the twentieth century. Immunocompromised individuals comprise a much larger proportion of the overall population as a result of advances in transplantation and cancer treatment as well as the global devastation caused by HIV. In addition, the incidence of atopic dermatitis has dramatically increased in recent decades. As supplies of vaccinia immune globulin (VIG) are very limited, it may be as or even more important to identify an effective chemotherapeutic agent for the treatment of vaccinia complications as for the treatment of smallpox. Fortunately, as the viruses are closely related, most antiviral agents with activity against one of these viruses is likely to also inhibit the other. New preclinical data (described below) support use of cidofovir 15 (CDV) for both treatment of smallpox and treatment of complications of vaccination.