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Title: Heterocyclic pyrophosphate analogues as potential antiviral agents
Author: Naylor, Matthew Alexander
ISNI:       0000 0001 3440 2102
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1985
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A series of novel and known heterocyclic pyrophosphate analogues have been synthesised and screened for activity against herpesvirus DNA polymerases, influenza A RNA transcriptase and calf thymus DNA polymerase a. A direct correlation between the compounds1 abilities to form complexes with zinc ions, as determined by a gel filtration method, and their effectiveness as inhibitors of the RNA transcriptase activity of influenza A virus and in some cases herpesvirus DNA polymerase, has been found. Introduction of 'soft' ligands such as nitrogen and sulphur into pyrophosphate and its analogues has resulted in improved antiviral activities, in particular, replacement of a phosphoryl group with a thiophosphoryl group has resulted in the discovery of some potent inhibitors of influenza A RNA transcriptase activity. 31P n.m.r. measurements have indicated that these compounds bind to zinc through sulphur, which could account for their increased antiviral activity if they bind in the same way to the essential zinc ion in viral polymerases. The most active of the heterocyclic pyrophosphate analogues, 5-(thiophosphonomethyl)-1(H)- tetrazole, showed improved efficacy against both influenza A RNA transcriptase activity and HSV-1 DNA polymerase activity over its non-thio analogue, 5-(phosphonomethyl)- 1(H)-tetrazole. Some nucleoside-51 esters of 5-(phosphonomethyl)- 1(H)-tetrazole were synthesised. These compounds were ineffective inhibitors of the RNA transcriptase activity of influenza and the DNA polymerase activity of herpesviruses, they did, however, exhibit some activity in tissue culture systems. These compounds may therefore act via a mechanism other than inactivation of viral polymerases, or be hydrolysed by cellular enzymes to give the free phosphonate. A strain dependence has been observed for the inhibition of influenza A virus in tissue culture by plaque reduction assay. Influenza A/WS was found to be the most sensitive of a series of strains tested. Some variation was also observed in the inhibition of different herpesvirus DNA polymerases with the compounds studied. The uptake of radiolabelled phosphonoacetate and 5-(phosphonomethyl)-1(H)-tetrazole into herpesvirus infected cells has been studied, and a virally-mediated increase in cell permeability to the compounds found to occur maximally 6-7 hours after infection. 5-(Phosphonomethyl)-1(H)-tetrazole shows a small increase in uptake over PAA into infected cells.
Supervisor: Not available Sponsor: Roche Products Limited ; Science and Engineering Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry ; RS Pharmacy and materia medica