Antiviral Agents

Abstract

Viral infections are among the greatest causes of human morbidity, and it is estimated that in developed countries more than 60% of all the episodes of human illness result from viral infections. High virus infection rates also occur among pets, livestock, and plants. The high morbidity and the resulting economic loss caused by these infections have generated tremendous efforts in recent years to develop antiviral agents. Since viruses propagate only within living cells, the development of antiviral drugs which would disrupt the viral replication without affecting the metabolism of the host cell was initially believed to be difficult, if not impossible. However, dramatic progress in viral molecular biology has now made it possible to identify enzymatic processes which are unique to virus‐infected cells. As a consequence, it is becoming feasible to design chemical compounds which identify infected cells, block a specific step in viral replication, and leave uninfected cells unharmed. The majority of antiviral drugs which are under clinical development today generally interrupt viral nucleic acid synthesis. These compounds possess considerable selectivity against virus‐induced enzymes. This article discusses agents exhibiting significant antiviral activity against viral infections in animal model systems. One of the simplest molecules found to inhibit the replication of DNA viruses in animals is phosphonoformic acid (PFA), CH 3 O 5 P. PFA has undergone clinical evaluation in humans for the treatment of recurrent genital herpes, hepatitis B viral infection, and acquired immunodeficiency syndrome (AIDS), as well as cytomegalovirus (CMV) infection of bone marrow and renal transplant patients. Levamisole (6‐phenyl‐2,3,5,6‐tetrahydroimidazol[2,1‐ b ]thiazole), C 11 H 12 N 2 S, was found to be effective against herpes virus infections in humans. Several pyrimidine bases have been found to inhibit herpes virus‐induced keratitis in rabbits, eg, 2‐amino‐4,6‐dichloropyrimidine, C 4 H 3 Cl 2 N 3 , and 1‐allyl‐6‐chloro‐3,5‐diethyluracil, C 11 H 15 ClN 2 O 2 . The most successful clinical antiviral agents belong to the nucleoside category. Nucleoside analogues with potent antiviral activity have been known since idoxuridine and trifluridine were shown to be efficacious against herpes keratitis more than 30 years ago. However, the therapeutic usefulness of these early nucleosides was limited because of mutagenic, teratogenic, carcinogenic, cytostatic, or cytotoxic side effects. Recently the specificity of antiviral action of this class of compounds has been significantly improved; potent and highly selective nucleoside antiviral agents have now been developed. These include cytosine derivatives, purine nucleoside derivatives, adenine derivatives, and acyclic purine nucleosides. Among agents active against RNA viruses, 1,2‐bis(5‐methoxy‐2‐benzimidazol‐2‐yl)‐1,2‐ethanediol, C 18 H 18 N 4 O 4 , was found to be active against an experimentally induced rhino virus infection in chimpanzees. However, the in vivo antiviral efficacy was accompanied by significant toxicity. Amantadine hydrochloride (1‐adamantanamine hydrochloride), \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{\rm{H}}{\rm{N}}{\rm{{\cdot{}}}}{\rm{HCl}}1710}$\end{document} , is a narrow‐spectrum agent active only against influenza A virus. It became the first antiviral drug available for systemic use in the United States when it was approved by the FDA in 1966 for use against Asian influenza. A structurally related drug, rimantadine hydrochloride, (α‐methyl‐1‐adamantanemethylamine hydrochloride), \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${{\rm{C}}{\rm{H}}{\rm{N}}{\rm{{\cdot{}}}}{\rm{HCl}}2112}$\end{document} , is widely used in Russia to treat influenza A virus. Lipophilic β‐diketones have exhibited significant in vivo activity against a number of RNA viruses, and adenosine and guanosine analogues have been found to be active against both RNA and DNA viruses. One of the broad‐spectrum antiviral agents that emerged from ICN Pharmaceuticals is an azole ribonucleoside, 1‐β‐ D ‐ribofuranosyl‐1,2,4‐triazole‐3‐carboxamide, designated as ribavirin, C 8 H 12 N 4 O 5 . Ribavirin has been studied in more animals and against more viruses than any other antiviral agent known today. It is active in cell culture against approximately 85% of all viruses studied. Viral strains susceptible to ribavirin have not been found to develop a resistance to the drug. The resistance against ribavirin is less likely because the drug exhibits multiple sites of antiviral action. Retroviruses as a class are often found to be responsible for persistent viral infections. Retroviruses are unique RNA viruses characterized by the transcription of their single‐stranded RNA into the double‐stranded DNA of the host cell using the viral enzyme reverse transcriptase. AIDS is an example of such a persistent and latent human viral infection. Following the identification of a retrovirus, HIV, as the etiological agent of AIDS, an intense effort has been made to identify drugs for the treatment or prevention of this debilitating, lethal disease. Several 2′,3′‐dideoxyribonucleosides of purine and pyrimidine were discovered to be potent inhibitors of HIV replication in vitro . Considerable data has also accumulated on in vitro antiHIV testing of acyclic and carbocyclic nucleoside analogues. 3′‐Azido‐3′‐deoxythymidine (retrovir, zidovudine, AZT), C 10 H 13 N 5 O 4 , 2,′3′‐dideoxycytidine (DDC), C 9 H 13 N 3 O 3 , and 2′,3′‐dideoxyinosine (DDI), C 10 H 12 N 4 O 3 , have become widely available for the treatment of AIDS and approved by the FDA for treatment of advanced AIDS cases.