Review Selective Anti-Herpesvirus Agents

Antiviral Chemistry & Chemotherapy 2013; 23:93–101 (doi: 10.3851/IMP2533)

Review Selective anti-herpesvirus agents

Erik De Clercq1*

1Rega Institute for Medical Research, KU Leuven, Leuven, Belgium

*Corresponding author e-mail: [email protected]

This review article focuses on the anti-herpesvirus agents foscarnet) or are under clinical development (CMX001 effective against herpes simplex virus, varicella-zos- [the hexadecyloxypropyl prodrug of cidofovir], the heli- ter virus and cytomegalovirus, which have either been case-primase inhibitor BAY 57-1293 [now referred to as licensed for clinical use (idoxuridine, trifluridine, brivu- AIC316], FV-100 [the valine ester of Cf 1743] and the din, acyclovir, valaciclovir, valganciclovir, famciclovir and terminase inhibitor letermovir [AIC246]).

Idoxuridine and trifluridine

The antiviral drug era started with the discovery of 5-fluorouracil [10,11]. Consequently, BVaraU was not idoxuridine (IDU) and trifluridine (TFT; Figure 1), further developed for the treatment of VZV infections, which were both launched, and are still used today, for whereas BVDU was marketed for this indication in sev- the topical treatment of herpetic eye infections (that is, eral European countries (including Germany, Italy and herpetic keratitis) due to herpes simplex virus (HSV). Belgium), with the warning, however, that, as a precau- IDU was first described by Prusoff [1] in 1959 as a tion, it should not be combined with 5-fluorouracil (or potential anti-tumour agent, whereas both IDU and TFT any of its prodrugs). were subsequently described as anti-HSV agents for the treatment of herpetic keratitis by Kaufman et al. [2–5]. Vidarabine Brivudin and BVaraU The first antiviral drug used for the systemic treatment of herpesvirus (HSV and VZV) infections was vidara- IDU and TFT could be considered as the starting point bine (Figure 4). Its clinical use was prompted thanks for the synthesis of various new 5-substituted 2′-deoxy- to the pioneering efforts of Whitley et al. [12–14]. Vid- uridine derivatives, the most prominent of this series arabine was later abandoned for a number of reasons, being brivudin (BVDU; Figure 2), which proved to be including relative insolubility in aqueous medium, and a highly specific inhibitor of HSV-1 as well as varicella- rapid deamination, by the ubiquitous adenosine deami- zoster virus (VZV) [6,7]. The arabinosyl counterpart of nase, to its inactive inosine counterpart, the principal BVDU (BVaraU; Figure 2) was subsequently found to reason being that it was surpassed in potency by acyclo- be equally potent as, if not more so than, BVDU against vir, which, incidentally, was discovered in the original VZV [8]. attempts to inhibit the rapid deamination of vidarabine. However, BVDU and BVaraU can be cleaved by hydrolases to release the free aglycon, 5-bromovinylu- Acyclovir racil (BVU), which acts as a powerful inhibitor of dihydrothymine dehydrogenase, the enzyme that catalyzes The antiviral drug era was greatly boosted by the dis- the hydrogenation of uracil and its 5-substituted deriv- covery of acyclovir (Figure 5) as a selective antiherpetic atives (such as 5-fluorouracil), the first step in the catab- agent [15]. In two papers that appeared in December olism of the uracil derivatives (Figure 3). The conver- 1977 [16] and April 1978 [17], acyclovir was described sion of BVDU to BVU primarily occurs in the liver (and as a selective antiherpetic agent, whose antiviral activity is reversible); that of BVaraU to BVU takes place in the depended on a specific phosphorylation by the virus- gastrointestinal lumen (by the gastrointestinal bacteria) induced thymidine kinase (apparently, the guanosine [9], is essentially irreversible, and has been shown to analogue acyclovir shared sufficient structural require- lead to some casualties, due to the enhanced toxicity of ments with thymidine to be recognized as a substrate by

the HSV-induced thymidine kinase, which also acts as (valaciclovir) also showed increased oral bioavailability a deoxycytidine kinase) [18,19]. Both BVDU and acy- and this finding [25] prompted the design of prodrugs of clovir were then shown to prevent the establishment of other antivirals as well. latent HSV infection in mice [20], and the molecular basis for the resistance of HSV against acyclovir was Famciclovir, valganciclovir, CMX001 and further characterized by Field and Darby et al. [21–23]. MIV-606 Valaciclovir Following the finding of increased oral bioavailability of valaciclovir, synthesized prodrugs included: famciclovir, In attempts to increase the aqueous solubility of acy- the double diacetyl precursor of 6-deoxy penciclovir (Fig- clovir (so as to make it applicable as eye drops [instead ure 7); valganciclovir, the valine ester prodrug of ganciclo- of ointment], or amenable to intramuscular [instead of vir (Figure 8); CMX001, the hexadecyloxypropyl prodrug intravenous] injection), amino acid esters of acyclovir of cidofovir (Figure 9), and MIV-606, the valomaciclovir were synthesized (that is, glycyl- and alanyl-acyclovir; stearate prodrug of H2G (Figure 10). All these antiviral Figure 6) [24]. As an additional bonus, the valine ester prodrugs fulfil an essential requirement for antiviral efficacy, that is they possess an increased oral bioavailability [26]. Single-day famciclovir (1,000 mg twice daily) Figure 1. The first antivirals: 5-substituted 2′-deoxyuridines has been recommended for recurrent genital prophylaxis [27], and valganciclovir and valaciclovir have been recommended for preemptive prophylaxis of cytomegalovirus O O (CMV) disease (after renal transplantation) [28]. I CF3 HN HN Foscarnet O N O N The smallest of all antivirals, which, for parenteral use, HO HO O O must be injected intravenously, is foscarnet (phosphonoformic acid [PFA]). PFA has been approved for the treatment of CMV infections, but can also be used, off HO HO label, for the treatment of HSV and VZV infections that are resistant to acyclovir. Characteristic for PFA is the IDU TFT Idoxuridine Triuridine presence of a phosphonate (P–C) bridge (Figure 11), a 5-lodo-2′-deoxyuridine 5-Triuoromethyl-2′-deoxyuridine hallmark that guarantees stability against (spontaneous Herpid®, Stoxil® Viroptic® and enzymatic) degradation and which is also found in the acyclic nucleoside phosphonates (that is, cidofovir, adefovir and tenofovir).

Figure 2. The (E)-5-(2-bromovinyl) component marking highly potent activity against varicella-zoster virus

O H Br O H Br

HN HN H H

O N O N HO HO O O HO

HO HO

BVDU BVaraU Brivudin Sorivudine (E)-5-(2-Bromovinyl)-2′-deoxyuridine Zostex®, Brivirac®, Zerpex®

Current state of the art: approved Figure 3. (E)-5-(2-bromovinyl)uracil inhibits degradation of antiherpesvirus drugs 5-fluorouracil

The antiviral agents have been the subject of a fact file BVDU BVaraU O first published by De Clercq et al. [29] in 2006, followed H Br by a second edition in 2008 [30–32]. For the treatment HN of herpesvirus infections (HSV, VZV, CMV and Epstein- H Barr virus), the systemic antiviral agents, as currently O N BVU approved by the US Food and Drug Administration, are H listed in Table 1. This list includes acyclovir, valaciclovir and famciclovir for the treatment of HSV and VZV O O infections, and ganciclovir, valganciclovir, cidofovir and F F foscarnet for the treatment of CMV infections (the only HN HN antisense oligonucleotide that ever received marketing Dihydrothymine O N O N approval as an antiviral drug was fomivirsen [30]: it H dehydrogenase H was approved for the topical treatment, upon intravit- 5-Fluorouracil 5-Fluoro-5,6- real inoculation, of CMV retinitis). Off label, cidofovir dihydrouracil and foscarnet are occasionally used for the treatment of severe HSV or VZV infections that have become resistant BVDU, brivudin; BVU, (E)-5-(2-bromovinyl)uracil. to acyclovir, valaciclovir or famciclovir (Table 1).

Figure 4. Vidarabine, the first antiviral drug for systemic use New anti-varicella-zoster virus drugs on the horizon: FV-100 NH In 2000, McGuigan et al. [33] described an exquisitely 2 N potent anti-VZV agent (Cf 1743), which was exclusively N active against VZV without any antiviral activity against any other virus including HSV; the prototype of this class N N of bicyclic furano pyrimidine nucleosides proved active HO against a large array of VZV strains at picomolar con- O HO centrations [34]. As previously carried out for acyclovir and ganciclovir, Cf 1743 (Figure 12) was converted to its valine ester, and this prodrug, dubbed FV-100, can OH be considered as the most potent and selective anti-VZV Arabinosyladenine agent reported to date [35]. Phase II clinical trials with Ara-A FV-100 are in progress. It should be administered once- Vidarabine ® daily (for 7 days) at a dose of 100, 200, 400 or 800 mg Vira-A (exact dosage still to be determined) [36], which compares favourably with valaciclovir that has to be given orally 3× daily at 1,000 mg. The helicase-primase inhibitor ASP2151 (Figure 13), Figure 5. Acyclovir, the ‘gold’-standard for treatment of assumed to be effective against VZV as well as HSV has herpes simplex virus infections been abandoned for further development [37].

New anti-herpes-simplex virus drugs on the O horizon: BAY 57-1293, AIC316, pritelivir N HN The helicase-primase inhibitor BAY 57-1293 (Fig- H N N N ure 14) was first described by Kleymann et al. [38,39] 2 HO in 2002. This compound, together with BILS 179 BS O [40], focused on a new target for new antiviral agents active against HSV. BAY 57-1293 was transferred Acyclovir 9-(2-Hydroxyethoxymethyl)guanine from Bayer to AiCuris for further development. It Zovirax® has been extensively studied for its potential to gen- erate drug-resistant mutants by Biswas and Field et

Antiviral Chemistry & Chemotherapy 23.3 95 E De Clercq

al. [41–52]. The clinical potential of BAY 57-1293 is CMX001, FV-100, BAY 57-1293 (AIC316) and restricted to HSV. It remains to be determined to what AIC246 (letermovir; Table 2). For an update on new extent BAY 57-1293 (AIC316) compares to the utility antivirals under development for the treatment of dou- of acyclovir, still the ‘gold’-standard for the treatment ble-stranded DNA virus (including HSV) infection, see of HSV infections. Dropulic and Cohen [53]. The development of maribavir (Figure 15) for the treatment of CMV infections has New anti-cytomegalovirus drugs on the been discontinued [54]. horizon: AIC246, letermovir Instead, AIC246 (letermovir; Figure 16), which inhibits HCMV replication via a mechanism that involves At present, there are four new candidate compounds the viral terminase but is distinct from that of mariba- for the treatment of HSV, VZV and CMV infections: vir [55], is now being pursued for its clinical potential

Figure 6. Amino acyl prodrugs of acyclovir

N HN

N H2N N HO O

Acyclovir

O O O N N N HN HN HN N N H N N N H2N N H2N N 2 H N CH CO O H2N CH CO O H2N CH2 CO O 2 O O O CH CH3 H3CCH3 Glycyl-acyclovir Alanyl-acyclovir Valaciclovir Valyl-acyclovir Valtrex®, Zelitrex®

Figure 7. Famciclovir, the orally bioavailable prodrug of Figure 8. Valganciclovir, the orally bioavailable prodrug of penciclovir ganciclovir

N O N O O N H N N N HN 2 N N H3C CO O HN HN H N N N 2 N N HO H2N N H2N N HO H2N CH CO O O O O CH CO HC3 CH3 OH CH3 OH OH Penciclovir Famciclovir Ganciclovir Valganciclovir Denavir®, Vectavir® Diacetyl 6-deoxy-9-(4-hydroxy-3- Cymevene®, Cytovene® Valcyte® hydroxymethyl-but-1-yl)guanine Famvir®

Figure 9. CMX001, the orally bioavailable prodrug of cidofovir

NH2 NH2

N N

O N O N O O

O P OH O P O (CH2)3 O (CH2)15CH3 OH OH HO HO Cidofovir Hexadecyloxypropyl-cidofovir Vistide® CMX001

Figure 10. The orally bioavailable H2G prodrug Figure 11. Foscarnet, the smallest of all antiviral drugs

N HN O H3C CH3 OH N CH H2N N HO P C O CH OH O C NH2 O O PFA C Foscarnet O (CH2)16CH3 Phosphonoformic acid Foscavir® Valomaciclovir stearate H2G prodrug MIV-606

Table 1. State of the art: currently approved systemic antiviral agents against herpesvirus infections

Drug HSV VZV CMV EBV

Acyclovir + + - - Valaciclovir + + - - Famciclovir + + - - Ganciclovir - - + - Valganciclovir - - + - Cidofovir OL OL + - Foscarnet OL OL + -

CMV, cytomegalovirus; EBV, Epstein–Barr virus; HSV, herpes simplex virus; OL, off label; VZV, varicella-zoster virus; +, approved; -, unapproved.

Antiviral Chemistry & Chemotherapy 23.3 97 E De Clercq

Figure 12. The bicyclic furanopyrimidine analogue Cf 1743 and its valine ester: exquisitely specific against varicella-zoster virus

O O

N N

O N O N HO H N CH CO O O 2 O CH HC3 CH3

OH OH

Cf 1743 FV-100 (valine ester of Cf 1743)

Figure 13. Helicase-primase inhibitor, effective against both Figure 14. Helicase-primase inhibitor, under development for herpes simplex virus and varicella-zoster virus herpes simplex virus

O H CH N 3 N O O N O N S NH N O S 2 S O N O N O CH3 BAY 57-1293 ASP2151 AIC316 Pritelivir

Development discontinued.

to treat cytomegalovirus infections. It exhibits excellent Tenofovir, a topical microbicide effective against in vitro inhibitory activity against HCMV laboratory HIV, as demonstrated by the CAPRISA study [62], was strains and clinical isolates [56], but no other betaher- recently reported to inhibit HSV-2 replication [63]. How- pesviruses (that is, rat cytomegalovirus, or human her- ever, tenofovir did so within the concentration range of pesvirus type 6 [HHV-6]) or a- or g-herpesviruses [57]. 20–200 mg/ml, whereas adefovir inhibited HSV-2 rep- Initial clinical results point to the successful treatment of lication within a concentration range of 0.5–50 mg/ml, multidrug-resistant human cytomegalovirus (HCMV) and cidofovir did so within the concentration range of disease with AIC246 [58]. 0.2–50 mg/ml [63].

Epilogue Acknowledgements

Anti-HSV agents may indirectly affect HIV-1 virus This review was originally based on the lecture presented titres: through its inhibitory effect on HSV replication, at the Symposium on Viruses and Antiviral Therapy (in valaciclovir may help reducing plasma HIV-1 levels in honour of Hugh J Field), Queens’ College, Cambridge, HIV-1/HSV-2-coinfected individuals [59–61]. UK, 23 March 2012.

Table 2. New antiviral agents at the horizon: in vitro antiviral activity

Agent Herpes simplex virus Varicella-zoster virus Cytomegalovirus

CMX001 + + + FV-100 - + - BAY 57-1293 (AIC316) + - - Maribavira - - + AIC246 (letermovir) - - + aDiscontinued. +, antiviral activity; -, antiviral inactivity.

Figure 15. Specific inhibitor of human cytomegalovirus Figure 16. Specific inhibitor of human cytomegalovirus

Cl N CH3 O N H N O Cl CH3 HO OH O N CF3

N N HO OH F N O Maribavir 1263W94 1-(β-L-Ribofuranosyl)-2-isopropylamino-5,6- dichlorobenzimidazole AIC246 Letermovir

Development discontinued.

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