Another ten stories in antiviral drug discovery (part C): “Old” and “new” antivirals, strategies, and perspectives

Abstract

The ten stories told here deal with (i) ribavirin as an inhibitor of IMP dehydrogenase and (ii) ribavirin, in combination with pegylated interferon, as the present "standard of care" for hepatitis C; (iii) S-adenosylhomocysteine hydrolase inhibitors as antiviral agents; (iv) new adamantadine derivatives for the treatment of influenza A virus infections; (v) 5-substituted 2'-deoxyuridines (i.e. IDU, TFT) for the treatment of herpes simplex virus (HSV) infections; (vi) acyclic guanosine analogues (e.g. acyclovir) for the treatment of HSV infections; (vii) OMP decarboxylase inhibitors (i.e. pyrazofurin) and CTP synthetase inhibitors (i.e. cyclopentenylcytosine) as possible antiviral agents; (viii) the future of cidofovir (and alkoxyalkyl esters thereof) and ST-246 as potential antipoxvirus agents; (ix) the two decade journey from tivirapine to rilpivirine in the ultimate therapy of HIV infections; and (x) the extension of the therapeutic application of tenofovir disoproxil fumarate (Viread) to the treatment of hepatitis B virus infection, in addition to HIV infection.

Exploiting the Anti-HIV-1 Activity of Acyclovir: Suppression of Primary and Drug-Resistant HIV Isolates and Potentiation of the Activity by Ribavirin

“…Moreover, the understanding of the molecular mechanism of ACV-mediated HIV-1 suppression allowed us to potentiate ACV suppressive activity by adding ribavirin, a known antiviral used in HCV treatment, which is capable of depleting the pool of intracellular dGTP (8).…”

“…In the present work, we used ribavirin to decrease the intracellular dGTP concentration and therefore increase the intracellular ACV-TP/dGTP ratio. Ribavirin inhibits IMP dehydrogenase, the enzyme that converts IMP to XMP, a key step in the de novo biosynthesis of GTP and dGTP (8,35). This strategy was used earlier to potentiate the antiviral activity of ACV, as well as those of ganciclovir and penciclovir, against herpesvirus and hepatitis B virus (8,28,44) and also of 2=,3=-dideoxyinosine (ddI) and 2=,3=-dideoxy-2,6-diaminopurine riboside (ddDAPR) against HIV (4,5).…”

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

“…The incidence of CMV infections such as retinitis has recently dropped drastically thanks to the successful treatment of AIDS with the current anti-HIV drugs. Yet the broad anti-DNA virus activity of (S)-HPMPC, similar to that of (S)-HPMPA (71), makes the compound potentially useful for the treatment of various DNA virus infections, poxvirus infections (74), and papilloma and polyoma virus infections (75,76). (S)-HPMPC would be more effective than smallpox vaccination against a lethal monkeypox virus infection (77).…”

Mutations Conferring Resistance to Viral DNA Polymerase Inhibitors in Camelpox Virus Give Different Drug-Susceptibility Profiles in Vaccinia Virus

“…Pre-and posthydration, as well as probenecid, are required to manage its potential nephrotoxicity. (S)-HPMPC is also used off-label for the treatment of polyoma-, papilloma-, adeno-, herpes-, and poxvirus infections (20,22,23). The search for orally available ANPs led to the discovery of CMX001, a lipid conjugate of (S)-HPMPC.…”