Antiviral drugs: current state of the art

doi:10.1016/S1386-6532(01)00167-6

Journal of Clinical Virology

Volume 22, Issue 1, August 2001, Pages 73-89

https://doi.org/10.1016/S1386-6532(01)00167-6 Get rights and content

Abstract

The chemotherapy of virus infections has definitely come of age. There are now 15 antiviral agents that have been formally licensed for the treatment of human immunodeficiency virus infections (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir) and several others, such as tenofovir disoproxil, emtricitabine, capravirine, emivirine, T-20 (pentafuside) and AMD3100 (bicyclam) are under clinical development. Lamivudine has been approved, and several other compounds (such as adefovir dipivoxil, emtricitabine and entecavir) are under clinical development, for the treatment of hepatitis B virus infections. Among the anti-herpesvirus agents, aciclovir, valaciclovir, penciclovir, famciclovir, idoxuridine, trifluridine and brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections, and ganciclovir, foscarnet, cidofovir, fomivirsen and maribavir (the latter in the developmental stage) are used in the treatment of cytomegalovirus infections. Following amantadine and rimantadine, the neuraminidase inhibitors, zanamivir and oseltamivir, have now become available for the therapy and prophylaxis of influenza virus infections, and so is ribavirin for the treatment of respiratory syncytial virus infections and the combination of ribavirin with interferon-α for the treatment of hepatitis C virus infections.

Introduction

After an initially slow start, the development of new antiviral agents has recently entered an accelerated growth phase. The current antiviral armamentarium actually comprises more than 30 drugs that have been officially approved, and 10 more may become available in the near future. Most of the approved drugs date from the last 5 years and at least half of them are used for the treatment of human immunodeficiency virus (HIV) infections. The other antivirals that are currently available are primarily used for the treatment of hepatitis B virus (HBV), influenza virus and herpesvirus [herpes simplex virus (HSV), varicella-zoster virus (VZV) and cytomegalovirus (CMV)] infections. For a total of 40 antiviral agents that are currently in clinical use, or considered for clinical use, I will describe the (i) chemical structure; (ii) spectrum of antiviral activity; (iii) mechanism of action; (iv) principal clinical indication(s); and (v) dosage and route of administration.

Section snippets

Nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs)

Zidovudine

•
Structure (Fig. 1): 3′-Azido-2′,3′-dideoxythymidine, azidothymidine (AZT), ZDV, Retrovir®.
•
Activity spectrum: HIV (type 1 and type 2).
•
Mechanism of action: Targeted at the reverse transcriptase (RT) of HIV, acts as chain terminator in the RT reaction, following intracellular phosphorylation to AZT 5′-triphosphate, and incorporation of AZT 5′-monophosphate at the 3′-end of the viral DNA chain.
•
Principal indication(s): HIV infection, in combination with other anti-HIV agents (such as

Anti-HBV compounds

Lamivudine

See above (Section 2). Lamivudine is used for the treatment of both HIV and HBV infections.

Adefovir dipivoxil

•
Structure (Fig. 22): Bis(pivaloyloxymethyl)ester of 9-(2-phosphonylmethoxyethyl)adenine or bis(POM)PMEA.
•
Activity spectrum: HIV (type 1 and type 2), HBV and herpesviruses (HSV, CMV, …).
•
Mechanism of action: Serves as oral prodrug of adefovir (PMEA) that is targeted at HIV RT and HBV RT, and acts as chain terminator, following intracellular phosphorylation to the diphosphate

HSV and VZV inhibitors

Aciclovir

•
Structure (Fig. 24): 9-(2-Hydroxyethoxymethyl)guanine, acycloguanosine, aciclovir (ACV), Zovirax®.
•
Activity spectrum: HSV (type 1 and type 2), VZV and some other herpesviruses.
•
Mechanism of action: Targeted at the viral DNA polymerase, acts as chain terminator, following intracellular phosphorylation to ACV triphosphate, and incorporation of ACV monophosphate at the 3′-end of the viral DNA chain. First the phosphorylation step is catalyzed by the virus-encoded thymidine kinase (TK),

Anti-influenzavirus compounds

Amantadine

•
Structure (Fig. 36): Tricyclo[3.3.1.1.^3,7]decane-1-amine hydrochloride, 1-adamantanamine, amantadine HCl, Symmetrel®, Mantadix®, Amantan®, …
•
Activity spectrum: Influenza A virus.
•
Mechanism of action: Blocks M2 ion channel, and thus prevents the passage of H⁺ ions that are required for the necessary acidity to allow for the uncoating process (decapsidation).
•
Principal indication(s): Influenza A virus infections (prevention and early therapy). Also used in the treatment of Parkinson's

Conclusions

A total of 40 antiviral compounds active against HIV, HBV, herpesviruses and influenza viruses have been the subject of this review. Only those compounds that have been licensed for clinical use or have proceeded to advanced clinical trials were discussed. Not included were those compounds that are still in preclinical or early clinical development for the treatment of HIV, HBV, herpesviruses, influenza virus infections or any other viral infections (i.e. RSV, HCV, picornaviruses, etc.).

The

Acknowledgements

E.D.C., who holds the Professor P. De Somer Chair of Microbiology at the Katholieke Universiteit Leuven School of Medicine, thanks Christiane Callebaut and Inge Aerts for their dedicated editorial assistance.

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^☆: Presented at the European Society for Clinical Virology Winter Meeting 2001, 11–13 January 2001, Ghent, Belgium.

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Antiviral drugs: current state of the art☆