Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2'-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2'-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.

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Approved Antiviral Drugs over the Past 50 Years

The complete DNA sequence of the Smith strain of murine cytomegalovirus (MCMV) was determined from virion DNA by using a whole-genome shotgun approach. The genome has an overall G+C content of 58.7%, consists of 230,278 bp, and is arranged as a single unique sequence with short (31-bp) terminal direct repeats and several short internal repeats. Significant similarity to the genome of the sequenced human cytomegalovirus (HCMV) strain AD169 is evident, particularly for 78 open reading frames encoded by the central part of the genome. There is a very similar distribution of G+C content across the two genomes. Sequences toward the ends of the MCMV genome encode tandem arrays of homologous glycoproteins (gps) arranged as two gene families. The left end encodes 15 gps that represent one family, and the right end encodes a different family of 11 gps. A homolog (m144) of cellular major histocompatibility complex (MHC) class I genes is located at the end of the genome opposite the HCMV MHC class I homolog (UL18). G protein-coupled receptor (GCR) homologs (M33 and M78) occur in positions congruent with two (UL33 and UL78) of the four putative HCMV GCR homologs. Counterparts of all of the known enzyme homologs in HCMV are present in the MCMV genome, including the phosphotransferase gene (M97), whose product phosphorylates ganciclovir in HCMV-infected cells, and the assembly protein (M80).

https://espace.library.uq.edu.au/view/UQ:255494/UQ255494_OA.pdf

Analysis of the complete DNA sequence of murine cytomegalovirus.

Mammalian Deoxyribonucleoside Kinases

After initial infection, human cytomegalovirus remains in a persistent state with the host. Immunity against the virus controls replication, although intermitent viral shedding can still take place in the seropositive immunocompetent person. Replication of cytomegalovirus in the absence of an effective immune response is central to the pathogenesis of disease. Therefore, complications are primarily seen in individuals whose immune system is immature, or is suppressed by drug treatment or coinfection with other pathogens. Although our increasing knowledge of the host-virus relationship has lead to the development of new pharmacological strategies for cytomegalovirus-associated infections, these strategies all have limitations-eg, drug toxicities, development of resistance, poor oral bioavailability, and low potency. Immune-based therapies to complement pharmacological strategies for the successful treatment of virus-associated complications should be prospectively investigated.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(04)01202-2.pdf

Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments

Summary: The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance.

Antiviral drug resistance of human cytomegalovirus.

HUMAN cytomegalovirus (HCMV) is a major pathogen in immunosuppressed individuals, including patients with acquired immune deficiency syndrome. The nucleoside analogue ganciclovir (9-(l,3-dihydroxy-2-propoxymethyl)-guanine) is one of the few drugs available to treat HCMV infections, but resistant virus is a growing problem in the clinic1 and there is a critical need for new drugs. The study of ganciclovir-resistant mutants has indicated that the selective action of ganciclovir depends largely on virus-controlled phosphorylation in HCMV-infected cells2–5. The enzyme(s) responsible have not been identified. Here we report that the HCMV gene UL97, whose predicted product shares regions of homology with protein kinases, guanylyl cyclase and bacterial phosphotransferases6–8, controls phosphorylation of ganciclovir in HCMV-infected cells. A four-amino-acid deletion of UL97 in a conserved region, which in cyclic AMP-dependent protein kinase participates in substrate recognition9, causes impaired ganciclovir phosphorylation. The implications of these results for antiviral drug development and drug resistance are discussed.

A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells

The average 50% inhibitory concentration (IC50) values for AD169 were 0.22 ± 0.09 μM 1263W94 and 5.36 ± 0.12 μM ganciclovir. For 35 human cytomegalovirus (HCMV) clinical isolates the average IC50 was 0.42 ± 0.09 μM 1263W94, and for 26 ganciclovir-susceptible HCMV clinical isolates the average IC50 was 3.78 ± 1.62 μM ganciclovir. Nine HCMV clinical isolates that were resistant to ganciclovir were completely susceptible to 1263W94.

Inhibition of ganciclovir-susceptible and -resistant human cytomegalovirus clinical isolates by the benzimidazole L-riboside 1263W94.

Three drugs are currently approved for treatment of cytomegalovirus (CMV) disease: ganciclovir, foscarnet and cidofovirl. Each has reasonably good antiviral activity, but significant toxicities limit their safety and effectiveness, and poor oral bioavailability further limits their clinical utility. In addition, drug resistance can develop during therapy and, because the mechanism of action of each of these drugs depends ultimately on inhibition of CMV DNA Polymerase, cross resistance among these drugs can occur. There is a need for safe and effective drugs that are orally bioavailable and directed against novel viral targets.

Michele Davis

Papers

A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells

Inhibition of ganciclovir-susceptible and -resistant human cytomegalovirus clinical isolates by the benzimidazole L-riboside 1263W94.

Development of novel benzimidazole riboside compounds for treatment of cytomegalovirus disease.