Antivirals: Current State of the Art

Erik De Clercq

Disclosures

Future Virology. 2008;3(4):393-405. 

Abstract

Most of the antiviral agents that have been approved, and are currently used in the treatment of virus infections, are targeted at HIV, HBV, herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV) and HCV or influenza virus. Additional compounds for HIV, HBV, HSV, VZV, CMV, HCV, influenza virus and several other viral infections, for example poxvirus (e.g., variola, vaccinia and monkeypox), respiratory syncytial virus, hemorrhagic fever virus (e.g., Lassa, Rift Valley and Ebola) and enterovirus (e.g., polio, Coxsackie and echo), are still in the experimental stage, that is, under clinical or preclinical development.

Introduction

Antiviral drug development is now progressing at the pace antibiotics were 30 years ago. At present, there are some 60 antiviral drug preparations that have been approved by the US FDA, almost half of which are used for the treatment of HIV infections. The remaining half are used for the treatment of HBV, herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), influenza and HCV infections. For the antiviral drugs formally approved by the FDA, see Table 1 .

For HIV infections, a total of 25 compounds are currently licensed for clinical use, which means that an average of more than one compound per year has been approved since the approval of zidovudine, the first anti-HIV compound, in 1987.[1,2] The need for urgent development of new anti-HIV compounds still remains because of the emergence of virus-drug resistance in heavily drug-experienced patients. Ideally, these new anti-HIV compounds should be directed at targets within the viral replicative cycle other than those that are already targeted by currently used anti-HIV drugs (i.e., reverse transcriptase or protease), but even so, they may be expected to lead to virus-drug resistance, given the notorious plasticity of HIV.

The compounds now available for the treatment of HIV infections fall into the following categories:

  • Nucleoside reverse transcriptase inhibitors (NRTIs)

  • Nucleotide reverse transcriptase inhibitors (NtRTIs)

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

  • Protease inhibitors (PIs)

  • Viral entry inhibitors (including coreceptor inhibitors [CRIs] and fusion inhibitors [FIs])

  • Integrase inhibitors (INIs)

In addition to those that have already been licensed for clinical use ( Table 1 ), other NRTIs, such as apricitabine and dexelvucitabine, NNRTIs, such as rilpivirine and dapivirine, and INIs, such as elvitegravir, are still under clinical development.[1] Structural formulae for those antiviral compounds that are under clinical development (or in the preclinical stage of development) are presented in Figure 1.

Figure 1.

Experimental antiviral compounds that are still in (pre)clinical development.

Treatment for HIV infection is routinely based upon the use of a combination of several drugs, consisting of one or two NRTIs (or one NRTI and one NtRTI), and one NNRTI, which may be further complemented by a PI, or, as the future may indicate, by CRI and/or INI. Since 2006 a triple drug combination with tenofovir disoproxil fumarate, emtricitabine and efavirenz has become available that can be administered orally as a single daily pill,[3] which represents a substantial difference from the initial HAART, which required more than 20 pills a day.

Although HBV follows a similar strategy for its replication (i.e., reverse transcription) as HIV, it lags behind in terms of antiviral drug development, which may at least in part be explained by the availability of an adequate vaccine for HBV (a vaccine for HIV is still lacking). For chronic HBV infections, current treatment strategies are based upon the use of lamivudine, adefovir dipivoxil, entecavir, telbivudine and (pegylated) interferon.[4] In addition, tenofovir disoproxil fumarate has recently been approved by the European Medicines Agency (EMEA; and expected to be approved soon by the FDA) for the treatment of chronic hepatitis B. The hexadecyloxypropyl (HDP) ester of tenofovir (CMX157) also offers substantial potential for the treatment of HIV and HBV infections.[5]

Furthermore, capsid binders have been described as a new potential drug class with a mechanism of action that is distinct from that of the nucleoside and nucleotide analogues.[6,7] HBV therapy may ultimately profit from the combination of different drugs with different modes of action.

While drug combination regimens are routinely used for the treatment of HIV infections, they have not yet gained acceptance for the treatment of HBV infections, although in both cases a similar rationale may be invoked (synergistic activity, decreased toxicity because of lower dosages of the individual drugs, and, most importantly, reduced risk for drug resistance development).

Although HCV is fundamentally different from HIV in terms of viral build-up and replication, and in the pathogenesis of the diseases that they account for (hepatitis C vs AIDS), the strategies that have been pursued for combating HCV are remarkably reminiscent of those applied previously for affronting HIV infections; in other words, inhibitors of the viral protease (aspartyl protease for HIV vs serine protease for HCV) and inhibitors of the viral polymerase (RNA-dependent DNA polymerase [reverse transcriptase] for HIV vs RNA-dependent RNA polymerase [RNA replicase] for HCV) and herewith associated, the possibility of targeting both enzymes with both nucleoside and non-nucleoside types of inhibitors, NRTIs and NNRTIs for HIV, and nucleoside RNA replicase inhibitors (NRRIs) and non-NRRIs (NNRRIs) for HCV, respectively.[1]

For the treatment of HCV infections, only (pegylated) interferon combined with ribavirin has been formally approved. The compounds under development for the treatment of HCV infections include the PIs boceprevir and telaprevir, among the NRRIs 2'-C-methyladenosine and 4'-azidocytidine derivatives, and, among the NNRRIs, a number of benzimidazole, thiophene, indole and benzothiadiazine derivatives.[1] As has been the rule for the treatment of HIV infections, it is likely that future treatment schedules for HCV infections will also be based upon drug combinations (PIs, NRRIs and NNRRIs), which may be extended to at least (pegylated) interferon as well.

Antiviral drug development for viral diseases other than HIV, HBV and HCV has been moving ahead at a (much) lower speed than the development of anti-HIV, -HBV and -HCV agents. For influenza virus infections most emphasis has been put on neuraminidase inhibitors,[8,9] and, to a lesser extent, matrix protein2 inhibitors; here, the RNA-dependent RNA polymerase (RNA replicase) should be further exploited as a target for chemotherapeutic intervention. The pyrazine derivative T-705 has been postulated to interact, following conversion to its 4-ribofuranosyl 5'-triphosphate form, with the influenza viral RNA replicase.[10]

Poxviruses, and in particular variola virus, the cause of smallpox, has engendered considerable interest because of bioterrorist threat, and several (candidate) drugs have been identified, including cidofovir,[11] which is targeted at the viral DNA polymerase;[12] ST-246, which is targeted at F13L, a viral envelope protein required for the production of extracellular virus[13] and which offers protection against orthopoxvirus infections in mice upon delayed treatment,[14] as well as monkeypoxvirus infections in ground squirrels upon early treatment;[15] and a number of compounds such as the 4-anilinoquinazoline CI-1033 (an ErbB-1 kinase inhibitor) and STI-571 (Gleevec®, an Abl-family kinase inhibitor), which interfere with the cellular signal transduction pathways and which were both found to be highly effective in protecting mice from a lethal vaccinia virus infection.[16,17]

Should there be a need to treat poxvirus infections (i.e., smallpox, monkeypox or the complications of vaccination with vaccinia virus), cidofovir remains, as of today, the primary choice.[11] In addition to cidofovir, several other acyclic nucleoside phosphonates (i.e., HPMPA, HPMPDAP, HPMPO-DAPy and cHPMP-5-azaC) have been identified as potent inhibitors of the replication of poxviruses such as camelpox, the orthopoxvirus most closely related to variola virus.[18] These acyclic nucleoside phosphonates could be readily conjugated with alkoxyalkyl esters (i.e., HDP or octadecylethyl)[19] so as to increase their oral bioavailability, and 1-O-octadecyl 2-O-benzylglycerol,[20] so as to target the lungs following oral administration. The hexadecylpropyl ester of cidofovir (CMX001) acts synergistically with ST-246 both invitro and invivo, which suggests that the combination of ST-246 and CMX001 may be useful in the treatment of orthopoxvirus infections.[21]

Among the respiratory tract viruses, respiratory syncytial virus (RSV) still remains a feared pathogen, especially in the newborn and elderly. Yet, progress towards anti-RSV compounds has been coming along slowly, the most advanced (currently in PhaseII clinical trials) being RSV 604, a benzodiazepine that targets the nucleocapsid protein of RSV.[22] Rhinovirus infections (the common cold), despite their socioeconomic impact, have received (surprisingly) little, if any, attention from either a preventive or therapeutic viewpoint, and for the SARS coronavirus, interest in developing antiviral drugs has disappeared concomitantly with the (apparent) disappearance of the virus.

For adenovirus, which causes respiratory as well as gastrointestinal infections, no (new) antiviral drugs have emerged; the only available treatment in immunosuppressed patients is off-label cidofovir. For the treatment of herpesvirus, and, in particular HSV infections, acyclovir and its oral prodrug, valaciclovir, and penciclovir and its oral prodrug, famciclovir, have remained the standard drug choices. No significant attempts have been undertaken to develop new drugs for the treatment of HSV infections (local or systemic).

Yet, now more than 5years ago, some helicase-primase inhibitors (i.e., BILS 179BS, BILS22BS and BAY 57-1293) were announced as potent inhibitors of HSV (type 1 and 2) replication,[23,24] and BAY 57-1293 was found to be superior to acyclovir in the treatment of experimental HSV infections in animal models [25,26]. Also, in comparison with famciclovir, BAY57-1293 conferred superior therapeutic activity against HSV-1 in BALB/c mice.[27] However, HSV-1 variants that are highly resistant to the helicase-primase inhibitors BILS22 BS[28] and BAY 57-1293,[29,30] have been isolated, and while these observations point to the specificity in the mode of action of these inhibitors, they also argue for careful monitoring for resistance, should helicase-primase inhibitors such as BAY57-1293 be brought forward in the clinic. The treatment of VZV infections (i.e., herpes zoster) is principally based upon acyclovir, valaciclovir and famciclovir in the USA and, in addition, brivudin, in many other (particularly European) countries. Currently in clinical development is the HCl salt of the 5'-valine ester (designated FV-100) of Cf1743, a very potent inhibitor of VZV replication.[31] Akin to valaciclovir and valganciclovir, the Cf1743 valine ester has increased oral bioavailability.[32] The parent compound (Cf1743)[31] is one of the most potent antiviral agents (with EC50 values against VZV in the subnanomolar concentration range in cell culture) that have ever been reported.[33] Astellas´ helicase-primase inhibitor ASP-2151 (WO2006082820, WO2006082821, WO2006082822), currently in PhaseII clinical trials, would also be active against VZV in the 2-digit nanomolar range [Pers. Comm.]. For the treatment of CMV infections, the current drug of choice is valganciclovir (the valine ester of ganciclovir, cidofovir and foscarnet are alternative drugs for the treatment of the more severe CMV infections). Maribavir, a specific anti-human CMV drug is currently advancing through PhaseIII clinical trials.[34] Maribavir is assumed to be a less toxic alternative to drugs currently used to treat CMV infections (i.e., valganciclovir, ganciclovir, cidofovir and foscarnet). As for the other anti-CMV compounds, development of maribavir resistance[35] should be monitored carefully.

Other, alternative drug candidates for the treatment of human CMV infections, which, like maribavir, may also interact with a late process (DNA maturation) during the viral replicative cycle, are the terminase inhibitors.[36–38]

For the treatment of human herpesvirus type6 (HHV-6), which is in much need of chemotherapeutic control measures, several possible candidate drugs have been identified[39,40] but no specific anti-HHV-6 agents have so far been taken into the clinic to evaluate their chemoprophylactic or therapeutic potential. Of the established anti-CMV drugs, valganciclovir is under current clinical investigation for the treatment of HHV-6 infection.

Hemorrhagic fever (HF) virus infections have been, and will remain, a threat for many years, given the diversity of the HF viruses, the diversity of their origin[41] and the diversity of the vectors that may transmit them. Most of the HF viruses belong to the negative-RNA virus (i.e., arena [Lassa], bunya [Rift Valley], filo [Ebola, Marburg]) families, and some investigational drugs have proven to be efficacious against experimental infections with arena- and bunyavirus infections (T-705)[42] as well as filovirus infections (3-deazaneplanocin A).[43] Recently, T-1106, an analogue of T-705, was found to be effective in a hamster model of yellow fever virus infection,[44] and more than 20years ago, ribavirin was shown to be an effective therapy for Lassa fever in humans,[45] but this observation has not been followed up.

For picornaviruses (enteroviruses [polio, Coxsackie A and B and echo]) no single antiviral drug has ever been approved, although pleconaril was once to be considered for this purpose. Yet, in the wake of the polio eradication program anticipated by the successful vaccination campaign, it would be wise to have some antiviral compounds at hand that may stop poliovirus infection should it re-emerge. A number of compounds, targeted at either the viral capsid (i.e., pirodavir), the viral protease (i.e., rupintrivir), viral RNA polymerase (i.e., 2'-C-methyl-adenosine), or the nonstructural proteins 2C (i.e., MRL-1237) or 3A (i.e., enviroxime) should be further considered as possible lead compounds for this purpose.[46]

Cellular enzymes such as S-adenosylhomocysteine (SAH) hydrolase and inosine 5'-monophosphate (IMP) dehydrogenase have remained interesting potential targets for broad-spectrum antiviral agents, such as 3-deazaneplanocin A and other SAH hydrolase inhibitors, and ribavirin and other IMP dehydrogenase inhibitors. They might find a therapeutic ‘niche´ in the treatment of those virus infections (i.e., arena and filo) that are otherwise not readily accessible to chemotherapeutic means.[47] In this context, it should be noted that for ribavirin the mode of action may be multipronged; while ribavirin is undoubtedly an inhibitor of IMP dehydrogenase,[48] its activity against some viruses (i.e., Hantaan virus) may correlate with the inhibitory effect of its 5'-triphosphate on the viral RNA polymerase rather than the interaction of its 5'-monophosphate with the IMP dehydrogenase.[49]

What about interferon, which has witnessed a renaissance with its usage in the treatment of HCV infections?[50] Last year interferon celebrated its 50th anniversary,[51] and is likely to remain a molecule for all seasons. Given its broad-spectrum antiviral (and immunomodulating), but primarily prophylactic rather than therapeutic, effects, interferon will continue to be an appealing commodity in the control (primarily prevention) of any newly emerging or re-emerging virus infection.

Future Perspective

At present, approximately half (i.e., 25) of the antiviral compounds currently used in the clinic are intended for the treatment of HIV infections, and this number is likely to increase, albeit at a slower pace than has been the case over the past few years. We are also likely to witness new compounds being approved for the treatment of HBV and, certainly, HCV infections. New compounds, now in (pre)clinical development, may, within the next few years, be launched for the treatment of HSV, VZV or CMV infections, and, possibly, RSV, influenza and poxvirus infections as well.

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