Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines

doi:10.1016/S0166-3542(87)80004-9

Antiviral Research

Volume 8, Issues 5–6, December 1987, Pages 261-272

Presented at the Fifth Annual ECP (European Organization for Cooperation in Cancer Prevention Studies) Symposium on Preventive Strategies for Cancers Related to Immune Deficiencies, held in Brussels. Belgium on 8–9 May 1987.

https://doi.org/10.1016/S0166-3542(87)80004-9 Get rights and content

Summary

Various 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and 2-phosphonylmethoxyethyl (PME) derivatives of purine [adenine (A), guanine (G), 2,6-diaminopurine (DAP), 2-monoaminopurine (MAP), hypoxanthine (HX)] and pyrimidine [cytosine (C), uracil (U), thymine (T)] have been evaluated for their antiviral properties. PMEDAP, (S)-HPMPA and (S)-cHPMPA showed the greatest inhibitory activity. As a rule, the PME derivates were much less inhibitory to VZV, CMV, vaccinia and adenovirus than the HPMP derivatives. However, PMEA, PMEDAP and PMEMAP showed marked and selective activity against the human immunodeficiency virus (HIV). (S)-HPMPA was selected for further evaluation in animal model infections. It proved efficacious in the topical treatment of HSV-1 keratitis in rabbits and cutaneous HSV-1 infection in hairless mice, and in the systemic treatment of both HSV-1 and vaccinia virus infections in mice.

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Citation Excerpt :
Furthermore, HSV strains resistant to both ACV and foscarnet due to the acquisition of mutations in both the TK and DNA pol have been described in the clinic [46,171]. Acyclic nucleoside phosphonates are DNA pol inhibitors that have a phosphonate group attached to the sugar moiety and therefore require only two activating phosphorylation steps, both executed by cellular kinases [50,172,173]. Because acyclic nucleoside phosphonates are independent of viral TK activity, they remain active against most ACVr HSV strains.
Herpes simplex viruses (HSV), the causative agents of recurrent orofacial and anogenital infections, can cause significant morbidity and mortality in both immunocompetent and immunocompromised individuals. In immunocompromised patients, HSV tends to be more persistent with chance of dissemination. The nucleoside analogue acyclovir has drastically improved the management of HSV infections although acyclovir resistant strains have been reported in the clinic. We performed a systematic search to summarize the prevalence data reported in both the immunocompetent and immunocompromised populations. Defining the global prevalence of acyclovir resistance in HSV infections is hampered by the high variability in methodology, patient selection, study design, and treatment history among the studies. Acyclovir resistant HSV is infrequent in the immunocompetent population (generally below 1%), irrespective of treatment history. Exceptions are infections at immune-privileged sites such as the cornea, where frequent recurrences and extensive acyclovir therapy favor the emergence of acyclovir resistance. Higher frequencies of acyclovir resistant HSV infections are reported among immunocompromised individuals, with the highest prevalence seen among hematopoietic stem cell transplant recipients. All antivirals approved for the treatment of HSV infections have the same target, i.e. the viral DNA polymerase, and cross-resistance to different antivirals has been described, complicating therapy of acyclovir resistant strains. In this review we will discuss acyclovir mode of action, mechanisms of resistance, prevalence of resistance, and alternative antiviral treatments for acyclovir resistant HSV infections.
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Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines

Summary

Antiviral Res.

Antiviral Res.

J. Virol. Methods

Selective inhibitory effect of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl(adenine and 2′-nor-cyclic GMP on adenovirus replication in vitro

Antimicrob. Agents Chemother.

In vitro activity of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine against newly isolated clinical varicella-zoster virus strains

Eur. J. Clin. Microbiol.

Topical treatment of cutaneous herpes simplex virus infection in hairless mice with (E)-5-(2-bromovinyl)-2′-deoxyuridine and related compounds

Antimicrob. Agents Chemother.

Antiviral nucleoside analogs

ISI Atlas of Science (Pharmacology)

Virus-drug resistance: thymidine kinase-deficient (TK−) mutants of herpes simplex virus. Therapeutic approaches

Annal. Ist. Sup. Sanita

Effect of interferon. polyacrylic acid, and polymethacrylic acid on tail lesions in mice infected with vaccinia virus

Appl. Microbiol.

Virus-drug resistance: thymidine kinase-deficient (TK⁻) mutants of herpes simplex virus. Therapeutic approaches