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The alternating copolymer riboadenylic-ribouridylic acid gained asignificant increase in ability to stimulate interferon production (2-to 20-fold) and cellular resistance (100-to 10,000-fold) both in vitro and in vivo upon substitution of phosphate by thiophosphate groups. The resulting nucleotide analog was also 10 to 100 times less sensitive to degradation by pancreatic ribonuclease, as determined byresidual antiviral activity.
In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO-T] prototype have been prepared. In these novel series, other NRTIs, an expanded range of linkers with different conformational freedom and other attachment sites for these linkers on the base part of the NRTI analogue have been explored. Moreover, in order to circumvent the dependence of the NRTI moiety of the heterodimer on activation by cellular nucleoside kinases, novel heterodimers in which the NRTI is bearing a masked monophosphate group at the 5'-position are described. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important for the eventual anti-HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl linker between the N-3 positions of the base of TSAO-T and d4T was approximately 5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.
status: Published
Although most of the recent attempts to develop new antiviral agents have been focussed on RNA viruses (in particular, HIV and hepatitis C virus), a few new compounds are now awaiting their entry into the field of DNA viruses, particularly poxviruses, such as variola virus, because of the bioterrorist context, and herpesviruses, such as herpes simplex virus and cytomegalovirus, where the market scene has for many years been dominated by acyclovir, penciclovir and ganciclovir and their respective orally bioavailable prodrugs: valaciclovir, famciclovir and valganciclovir. Here, we review the current 'state of the art' with old compounds ready to rotate off and new compounds eagerly awaiting to appear on the continuously evolving scene of antiviral drug development.
