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Recent highlights in the development of new antiviral drugs

Erik De Clercq

Twenty antiviral drugs, that is about half of those that are penciclovir, idoxuridine and trifluridine are used (the
currently approved, are formally licensed for clinical use in the latter three only topically) in the treatment of herpes
treatment of human immunodeficiency virus infections simplex virus (HSV) and/or varicella-zoster virus (VZV)
(acquired immune deficiency syndrome). The others are used in infections; ganciclovir, valganciclovir, foscarnet, cidofovir
the treatment of herpesvirus (e.g. herpes simplex virus, and fomivirsen (the latter only by intravitreal injection)
varicella zoster virus and cytomegalo virus), hepatitis B virus, have proven useful in the treatment of cytomegalovirus
hepatitis C virus or influenza virus infections. Recent (CMV) infections in immunocompromised patients (i.e.
endeavours have focussed on the development of improved AIDS patients that have CMV retinitis). Following the
antiviral therapies for virus infections that have already proved progression of amantadine and rimantadine (matrix 2
amenable to antiviral drug treatment, as well as for virus protein blockers) onto the market, the neuraminidase
infections for which, at present, no antiviral drugs have been inhibitors zanamivir and oseltamivir have become avail-
formally approved (i.e. human papilloma viruses, adenoviruses, able for the therapy (and prophylaxis) of influenza virus
human herpesvirus type 6, poxviruses, severe acute respiratory infections. Ribavirin has been used (topically as an aero-
syndrome coronavirus and hemorrhagic fever viruses). sol) in the treatment of respiratory syncytial virus infec-
tions, and the combination of ribavirin with (pegylated)
Addresses interferon-a has received increased acceptance for the
Rega Institute for Medical Research, Katholieke Universiteit Leuven, treatment of hepacivirus (hepatitis C virus; HCV) infec-
Minderbroedersstraat 10, B-3000 Leuven, Belgium
tions.
Corresponding author: De Clercq, Erik (erik.declercq@rega.kuleuven.be)
There are, however, several other important virus infec-
tions for which no antiviral drugs have been developed;
Current Opinion in Microbiology 2005, 8:552–560 even for those that are amenable to antiviral drug therapy
This review comes from a themed issue on there is still considerable room for improvement in terms
Antimicrobials of higher potency and/or increased selectivity or safety. In
Edited by Christopher Walsh and Malcolm GP Page this review, I will highlight some of the most recent
approaches towards the treatment of human papilloma
Available online 24th August 2005
virus (HPV) infections, adenovirus infections, HSV and
1369-5274/$ – see front matter VZV infections, human herpesvirus type 6 (HHV-6)
# 2005 Elsevier Ltd. All rights reserved. infections, poxvirus infections, hepacivirus infections,
corona virus infections (i.e. severe acute respiratory syn-
DOI 10.1016/j.mib.2005.08.010
drome [SARS]), influenza virus infections, hemorrhagic
fever virus infections and HIV infections (AIDS).

Introduction Human papilloma virus infections
Of the 40 antiviral drugs that have been formally Although cidofovir, which is also known as (S)-1-(3-
licensed for clinical use [1], 20 are used in the treatment hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC;
of human immunodeficiency virus (HIV) infections Figure 1), is formally licensed only for the intravenous
(acquired immune deficiency syndrome; AIDS). The treatment of CMV retinitis in AIDS patients, ‘off label’ it
anti-HIV compounds fall into five categories: first, the has been used successfully in the systemic and topical
nucleoside reverse transcriptase inhibitors (NRTIs), zido- treatment of several other DNA virus infections, such as
vudine, didanosine, zalcitabine, stavudine, lamivudine, polyoma-, papilloma-, adeno-, herpes- and pox-virus [2].
abacavir and emtricitabine; second, the nucleotide Particularly striking are the effects that have been obtained
reverse transcriptase inhibitor, tenofovir disoproxil fuma- with cidofovir (topical gel application or direct intralesional
rate; third, the non-nucleoside reverse transcriptase inhi- injection) in the treatment of HPV-associated papilloma-
bitors (NNRTIs), nevirapine, delavirdine and efavirenz; tous lesions, such as hypopharyngeal and esophageal
fourth, the protease inhibitors (PIs), saquinavir, ritonavir, papilloma, laryngeal papilloma, recurrent respiratory papil-
indinavir, nelfinavir, amprenavir, lopinavir (combined at a lomatosis (in children), anogenital HPV infections (i.e.
4 to 1 ratio with ritonavir), atazanavir and fosamprenavir; condylomata acuminata), bowenoid papulosis (perianal
and fifth, the fusion inhibitor, enfuvirtide. Lamivudine intraepithelial neoplasia), cervical and vulvar intraepithe-
and adefovir dipivoxil have been approved for the treat- lial neoplasia grade III, recalcitrant warts (including plantar
ment of hepatitis B virus infections. Of the anti-herpes- warts), and other mucocutaneous HPV lesions that did
virus agents, acyclovir, valaciclovir, famciclovir, brivudin, not respond to conventional therapies [3]. In most of

Current Opinion in Microbiology 2005, 8:552–560 www.sciencedirect.com

8:552–560 .sciencedirect. Recent highlights in the development of new antiviral drugs De Clercq 553 Figure 1 Structures of the compounds indicated in text.com Current Opinion in Microbiology 2005. www.

sciencedirect. exquisitely active against VZV. 8:552–560 www. they are unlikely to enhance the toxicity of are generally self-limiting.4-diamino-6-[3-hydroxy-2-phosphonomethoxy)pro. This novirus replication. of its degradation product. activity. PMEG and cPr degradation of 5-fluorouracil).9]. although tumor suppressor proteins p53 and pRb (which are neu. HPV-infected cells [3]. This effect might be related drug of penciclovir) and brivudin (BVDU). (HPMPC) and HPMPA should be evaluated in the future for their potential to treat adenovirus infections in humans. the N7-substituted mase complex. poxy]pyrimidine (HPMPO-DAPy. Also. bicyclic furo(2. valaciclovir tained that cidofovir specifically ‘kills’ HPV-positive cells (the oral prodrug of acyclovir).30 -dideoxycytidine. adenovirus infections can be shown not to interfere with the dihydropyrimidine dehy- severe and life-threatening. BAY 57-1293 (Figure 1). i. S-2242. respectively) in patients that have herpes zoster or HSV-1 infections. Figure 1) have proved to be potent and selective inhibitors of the in vitro New anti-HSV agents that target the viral helicase–pri- replication of adenoviruses [4]. famciclovir (the oral pro- by the induction of apoptosis. methyl)purine S-2242 and the 20 . in that they inhibit only VZV replication and not the replication of any other viruses such as HSV. whereas no anti-adenovirus activity complex comprises three viral proteins — the HSV UL5. BILS 179BS and. allogeneic hematopoietic stem to the free pyrimidine base. BVDU can potentiate propyl-2. ase. Figure 1) and excess of 100 000. the ether lipid ester (i. a virtually complete and durable resolution of cation in vitro at significantly lower concentrations and with the lesions was achieved following the application of significantly higher selectivity indices than those noted for cidofovir (as a 1% gel or cream). Cf 1743 [Figure 1]) do not have this drawback. but in immunocompromised 5-fluorouracil for two reasons: first. are able to specifically induce apop. cules that interact with the formation of the HSV DNA Current Opinion in Microbiology 2005. These alovudine (30 -fluoro-20 . In addition to cidofovir.e. for 5-fluorouracil (which is a cytostatic agent used in the example 9-(2-phosphonylmethoxyethyl)guanine (PMEG. BVU.30 -dideoxythymidine. Cf 1369.30 -dideoxynucleoside were recently reported to have in vivo efficacy in animal analogues zalcitabine (20 . 50% inhibitory concentration against viral replication) in ylmethoxypropyl)adenine (HPMPA. like cidofovir.554 Antimicrobials these cases. acyclovir. potential for the treatment of VZV infections. With a In addition to cidofovir. Although the BCNAs have proven to be as active.e. Cf 1368. and. This by itself Also. such as the thiazolylphenyl derivatives acyclic nucleoside 2-amino-7-(1. and Cf 1742 and Adenovirus infections Cf 1743 are 10-fold more active against VZV than BVDU Adenovirus infections in immunocompetent individuals [6. was observed for several other antiviral compounds. the toxicity of 5-fluorouracil (through inhibition of dihy- which. ddC) and models of HSV-1 and HSV-2 infections [8. such UL-8 and UL52 gene products — which together unwind as ribavirin. The newly discovered PMEDAP are currently being investigated for their poten. A further extension of this approach involves the mole- these compounds were found to inhibit adenovirus repli. also known compounds appear to function by enhancing the affinity as FddT and FLT) were found to inhibit in vitro ade. Although the (compelling) evidence for the effectiveness Herpes simplex virus and varicella-zoster of cidofovir against HPV infections stems from in vivo virus infections observations in an increasing number of patients. they are not degraded patients and. its use is restricted to tralized by the oncoproteins E6 and E7.com . the latter was cell transplant recipients. 1293 is superior to all other compounds currently used for the treatment of HSV infections [10]. At present. HSV and/or VZV infections include acyclovir. penciclovir and brivudin the double-stranded viral DNA and generate the primer/ [4]. of the helicase–primase complex for the HSV DNA. ddC and FLT in both experi. Cf 1742 [Figure 1] and lesions. The latter is to the ability of cidofovir to restore the function of the only available in some European countries. cidofovir (HPMPC) drogenase that initiates the catabolism of 5-fluorouracil appears to be the only licensed antiviral drug that can be [6]. in vitro Standard antiviral drugs currently used in the treatment of experiments with HPV-infected keratinocytes have ascer. a key enzyme in the tosis in HPV-infected keratinocytes. templates for DNA synthesis by the viral DNA polymer- HPMPO-DAPy. dropyrimidine dehydrogenase. the parent compounds (HPMPC and HPMPA) [5]. It might be worthwhile to further examine HPMPA. a few other acyclic nucleoside selectivity index (ratio of 50% cytotoxic concentration to phosphonates such as (S)-9-(3-hydroxy-2-phosphon. the BCNAs offer an unprecedented (S)-2. treatment of certain cancers) because through the release Figure 1) and 9-(2-phosphonylmethoxyethyl)-N6-cyclo. there BVDU cannot be administered concomitantly with are several other acyclic nucleoside phosphonates.3-d)pyrimidine nucleoside analogues tial in the treatment of HPV-associated papillomatous (BCNAs. It has been claimed that the antiviral potency of BAY- mentally and clinically oriented studies.7]. hexadecyloxypropyl [HDP] validates the further pursuit of helicase–primase inhibi- and octadecyloxyethyl [ODE]) prodrugs of cidofovir tors for the treatment of HSV infections. BCNAs are extremely selective in their anti-VZV successfully used to treat adenovirus infections [3].6-diaminopurine (cPr PMEDAP. foscarnet. Figure 1). in particular. especially. and second.3-dihydroxy-2-propoxy.

and. with the exception of HHV-6 and HHV-7. cidofovir has other non-structural proteins such as the NS3-encoded shown high efficacy in protection of mice from a lethal NTPase–helicase and serine protease and the NS5B- respiratory infection of either vaccinia or cowpox. CMV423 must Hepacivirus infections (hepatitis C) be targeted at an event that follows viral entry but that The present therapy for chronic hepatitis C consists of precedes viral DNA replication. but this length of time might be reduced to 24 weeks The family of poxviridae encompasses orthopoxviruses for patients infected with HCV genotypes 2 or 3. valganciclovir.sciencedirect. ment of vaccinia and cowpox infections [20]. Protein–protein or intranasal (aerosolized) dose. agent targeted at a phosphoprotein encoded by the non- ogues (i. 8-methyladenosine and idoxuridine) structural NS5A gene of the HCV genome [25].e. it viral DNA polymerase and can be considered (following would be useful to have an orally active drug at hand that phosphorylation) as substrate analogues (except for fos. could be self-administered [18]. In as antiviral drugs. In particular. daily) [22. as well as in the treatment of the complications been formally approved for the treatment of HHV-6 of vaccinia that can arise in immunocompromised infections [12]. HHV-6 and HHV-7 [14]. significantly enhance inhibition of orthopoxvirus replica- ing HCMV). CMV423 was also found pegylated interferon (IFN)-a2a (180 mg. humans. 8:552–560 . vaccinia. orf) and mollusciviruses (e.23]. prophylaxis) and consist of ganciclovir. has been increasingly recognized as mised patients (reviewed by De Clercq [17]).6. However. They exhibit broad-spectrum anti. In this (e. In an outbreak of smallpox. developed as potential (oral) drugs for the prophylaxis lines. tion (i. HDP-CDV has also proven effective in the treatment of lethal We have recently discovered a new antiviral agent. which inhibits the inter. unlike for CMV infections. When given Their lack of activity against HHV-6 is owing to a single orally. and nucleotide analogues (including HPMPC [cidofovir] and HPMPO-DAPy) are effective in various animal mod.g.e. acyclovir. modulator. S2242. which acts as a pyrophosphate analogue).7. In addition to the NS5A gene product. vaccinia virus respiratory infections in mice [21]. act as non-nucleoside inhibitors of herpesvirus and treatment of variola virus infection (Figure 1) [18]. Cidofovir has demon- interactions constitute a new target for the design of strated high effectiveness in the treatment of dissemi- antiviral agents to be further explored for their potential nated progressive vaccinia in athymic-nude mice [16]. Several nucleoside anal. to a lesser extent. hexadecy- carnet.e. higher potency and lower cytotoxicity. more. variola. cowpox. These data an important pathogen in immunocompromised patients indicate that cidofovir will be effective in the therapy and (in which it might cause life-threatening complications). Therefore. ribavirin is assumed to act as an immuno- pox). HDP-CDV and ODE- lizine-1-carboxamide. cidofovir has been used successfully by both the topical and intravenous route in the treatment of orf and Human herpesvirus type 6 infections recalcitrant molluscum contagiosum in immunocompro- HHV-6. HDP-CDV and ODE-CDV were as effective as amino acid change in the conserved domain III of the cidofovir is when administered parenterally for the treat- HHV-6 DNA polymerase [13]. there are a few els of poxvirus infections [15]. after administration of a single systemic (intraperitoneal) action between UL-30 and UL42) [11]. DNA polymerases. once weekly) to inhibit total cellular protein tyrosine kinase activity. combination.g.com Current Opinion in Microbiology 2005. www. Further- CMV423 (2-chloro-3-pyridin-3-yl-5.8-tetrahydroindo. BP5. Recent highlights in the development of new antiviral drugs De Clercq 555 polymerase complex (i. monkeypox and camel. the 4-oxo-dihydroxyquino. valaciclovir. vaccinia and cowpox) in vitro [19]. as cidofovir is a phosphonate analogue it has and foscarnet. was concluded that CMV423 exerts its activity against This treatment regimen produces a sustained virologic HHV-6 through inhibition of a cellular process that is response in at least 50% of the patients infected with crucial in the early stage of viral replication and that might HCV genotype 1 and 2 (and 80% of the patients infected involve protein tyrosine kinase activity [14]. cidofovir However. loxypropyl-cidofovir (HDP-CDV) and octadecyloxy- ethyl-cidofovir (ODE-CDV) were designed and Another class of compounds. These alkyloxyalkyl esters of cidofovir were found to viral activity against most human herpesviruses (includ. The drugs clinically used against patients inadvertently inoculated with the smallpox vac- HHV-6 are the same as those used in CMV therapy (or cine (vaccinia) [17]. parapoxviruses (e.g. It combined with ribavirin (1000 or 1200 mg. like CMV. Com. Figure 1). even encoded RNA-dependent RNA polymerase (RdRp. which demonstrated CDV proved highly efficacious in a lethal mousepox potent and selective in vitro activity against all three human (aerosol ectromelia virus) model. prophylaxis of smallpox (variola) and related poxviruses in however. its anti- viral action appeared to be cell-dependent. further attesting the b-herpesviruses — CMV. whereas the IFN would act as an antiviral molluscum contagiosum virus). Patients infected with HCV genotype 1 should be treated for at least 48 weeks Poxvirus infections [24]. All these compounds are targeted at the limited oral bioavailability. CMV423 showed a in the oral therapy and prophylaxis of poxvirus infections. no compounds have humans. with another genotype of HCV). when administered orally. potential usefulness of other lipid prodrugs of cidofovir pared to ganciclovir and foscarnet.

much Coronavirus infections emphasis has been recently put on the chemotherapy There are several HCV proteins encoded by the SARS (and prophylaxis) of influenza virus infections. and it has been fusogenic mechanism of HIV is similar to that of SARS. in the past they did not gain wide CoV (as well as for other enveloped viruses. including acceptance. these inhibit the [39]. There is no shortage of small molecules Equally attractive as a target for the development of HCV that are active in the 1–10 mM concentration range [38]. particularly for amantadine. expression by type-1 pneumocytes. a variety of ‘old’ and ‘new’ compounds have RNA has been provided for the protease inhibitor BILN been reported to inhibit the in vitro replication of SARS- 2061 (Figure 1) [26]. now two years after its first sidered as a surrogate virus for HCV [27. Although ribavirin is active in vitro against the replication CoV S protein mediates infection of permissive cells by of influenza virus. There are.com . blocking SARS-CoV infection. combined with the fact that no vaccination is available for the latter. The matrix (M2) hydrogen ion channel blockers aman- ciation with the SARS-CoV receptor ACE2 [34]. for example the NTPase/helicase and RNA repli- Proof-of-principle that compounds targeted at the NS3 case. thus. tadine and rimantadine have been used for many years for tion to ACE2. such a structural basis still has to be elaborated. Knowledge of the crystal structure of the SARS-CoV main Influenza virus has adopted a unique replication strategy: protease offers a solid basis for rational drug design of it uses one of its surface glycoproteins. and pegylated IFN-a was recently shown to reduce replication of BVDV with high efficiency [29]. three classes of compounds that could be targets for chemotherapeutic intervention: the spike (S) considered for this purpose: ribavirin. and a human monoclonal antibody to the S1 domain was found to neutralize SARS-CoV by blocking its asso.g. protease could reduce plasma concentrations of HCV Meanwhile. In addi. the SARS-CoV main protease (also known as the rimantadine. We have apparition (and subsequent disappearance). Highly selective but whether any of these molecules will prevent or antiviral agents targeted at the viral RNA replicase have suppress the infection in vivo remains to be established. the C-type lectin CD209L (also called the prophylaxis and therapy of influenza A virus infec- L-SIGN) was identified recently as a receptor for SARS. other viral (or cellular) protein-mediated processes [31]. amantadine and protein. these non-nucleo- side RdRp inhibitors are likely to be combined with the Influenza virus infections ‘nucleoside’ RdRp inhibitors. Given the persistent epidemics of influenza A strains albeit a relatively weak inhibitor of BVDV and HCV. to the extent that the they are not active against influenza B. only the neuraminidase inhibitors zanamivir virtide. mainly for the following reasons: they rapidly Ebola). and oseltamivir are practically available for the therapy and/or prophylaxis of influenza A and B virus infections. A 193-amino acid fragment of the aerosol formulation in patients (primarily young infants) S protein (that corresponds to amino acid residues 318– that are at (high) risk of bronchopneumonitis caused by 510) was found to block S protein-mediated infection respiratory syncytial virus infection. For other potential envisaged as targets for inhibitors of HCV replication.5-c]pyridine [also known as BPIP. inhibitors is the HCV RNA replicase. hemagglutinin Current Opinion in Microbiology 2005. might be a target for lead to the emergence of drug-resistant virus mutants. However. future treatment of HCV infections. a pestivirus that could be con. possibly. Should SARS re-emerge. 8:552–560 www. prophylaxis and early post-exposure management of dazo[4. coronavirus (SARS-CoV) that could be considered as in principle. tions. six-helix bundle formation). [33].556 Antimicrobials which is also known as RNA replicase) that could be SARS-CoV protease inhibitors [36]. express the SARS-CoV receptor angiotensin-converting it has been developed for inhalation as a small-particle enzyme 2 (ACE2) [32]. In the infected experimentally with SARS-CoV [40]. CoV when present in relatively high concentrations (1 mM) [37]. and oseltamivir (Figure 1). like ACE2. new congeners have been derived that attendant pulmonary damage in cynomolgus macaques act equally efficiently against HCV replication. avian influenza A strain H5N1. with regard to heptad repeat interactions and side effects on the central nervous system. it has not been actively pursued for the controlling the interaction of its S1 domain with cells that management of influenza virus infections in vivo. is H3N2 and H1N1 and the threat of a pandemic with the N4-hydroxycytidine [30]. An example of the latter. From this viral replication and excretion. CD209L. At present. targets. that they exert CoV (e. to decrease viral antigen class of compounds. Instead. it should be feasible to develop SARS-CoV fusion inhibitors analogous to enfu. Figure 1]) that SARS: IFN-a inhibits SARS-CoV replication in vitro act as ‘non-nucleoside’ RdRp inhibitors. based on a different structure–activ. and to reduce the ity relationship. pegylated form of IFN-a would be a logical choice for the prototype 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imi. The SARS. been described to inhibit the replication of bovine viral diarrhoea virus (BVDV). the NTPase/helicase. Also.g. which is used for treatment of HIV [35]. perhaps the recently described a novel series of compounds (e. the RNA-depen. and the neuraminidase inhibitors zanamivir 3C-like protease).sciencedirect. dent RNA polymerase (RdRp) and.28]. demonstrated.

Also. they therefore decrease the requirement for antibiotics. nematode anticoagulant protein C2. When used prophylacti. a reduction in virus exerts its antiviral activity in vitro appears to be based on transmission to household or healthcare contacts. yellow fever and dengue). different approach towards the treatment of Ebola should be stockpiled to affront a potential influenza A virus infection is based on the use of a recombinant pandemic in the future. whether pegy. HIV has generated more efforts towards antiviral drug Congo and Hantaan) and filoviridae (i.e. efficacy.e. nistered as a single dose on the first or second day after tamivir [43]. target specific novel and ampligen.com Current Opinion in Microbiology 2005. For the treatment of Ebola (or Marburg) virus infections. Recent highlights in the development of new antiviral drugs De Clercq 557 (H).e. forcing the aminidase inhibitors block the release of newly formed RNA virus into gaining a lethal accumulation of errors.49]. Lassa. and in particular oseltamivir. including dengue Some compounds. ribavirin (Figure 1) bicides: they show marked stability at relatively low pH can be accredited with some efficacy in experimental and high temperatures for prolonged time periods. terminal sialic acid (N-acetylneuraminic acid). Neur. they www. development than any other virus. nomethoxy)alkoxy]-2. At present. new prophylaxis and/or therapy of flavivirus infections as they acyclic nucleoside phosphonates (i. Various mechanisms of action another surface glycoprotein. they significantly reduce the number of new cases S-adenosylhomocysteine hydrolase inhibitors (such as that have influenza. This strategy Hemorrhagic fever virus infections targets the disease process rather than viral replication The most important hemorrhagic fever viruses fall within [52]. (pre)clinical investigation target the same specific viral lated or not. and a inhibition of inosine 5’-monophosphate dehydrogenase reduction in the frequency and severity of complications [41. arenaviridae (i.51]. Rift Valley. DAPy and PMEO-DAPy [55]) and deoxythreosyl nucleo- tal flavivirus encephalitis model in severe combined side phosphonates (i. which can the Ebola virus-infected animals [50. vaginal) microbicides. A totally be more conveniently administered as oral capsules. Crimean. Marburg). the plant lectins (i. IFN-a.54]. For flaviviruses (such as The benefits offered by the neuraminidase inhibitors are yellow fever) and paramyxoviruses (such as parain- substantial. and prob- (H1N1) virus [44]. Gua. Zanamivir and oseltamivir are both able to infection. they lead to a fluenza). Although resistance to neuraminidase carbocyclic 3-deazaadenosine and 3-deazaneplanocin inhibitors can develop [42]. also almost all the mice against a lethal Ebola virus infection. the 6-[2-(phospho- decrease virus-induced morbidity (paralysis) and mortal.e. In recent years.e. and would. and IFN inducers. cally. we have witnessed the development of novel approaches as Prospects for the therapy of flavivirus infections are not well as newly emerging (candidate) drugs for anti-HIV overwhelming [37]. virus. offer an appreciable potential for the viral proteins. but it remains to be demonstrated anilide UC-781 are being actively pursued as topical whether or not this antisense approach also offers in vivo (i. to cleave have been proposed to explain the antiviral activity of off the terminal sialic acid of the host cell receptor. and against Lassa fever [37]).e. has been described to inhibit the replica- tion of several RNA viruses in vitro. a potent inhibitor of tissue factor-initiated blood coagulation. neuraminidase.48]. (such as sinusitis and bronchitis). Ebola.41]. such as poly(I)poly(C) proteins as the licensed compounds. such as cyanovirin-N and thiocarbox- virus types 1–4 [46]. phosphonomethyldeoxythreosyl- immunodeficient mice [45]. According to this hypothesis. Another approach. The most fascinating of these is the theory of allowing the virus particles to leave the cells after the ‘error catastrophe’ [47. Figure 1) might be worth pursuing: even when admi- naturally occurring resistance to either zanamivir or osel. virus particles.e.4-diamino pyrimidines PMPO- ity (caused by progressive encephalitis) in an experimen. cellular uptake. ribavirin would act as an RNA virus mutagen. based adenine [PMDTA] and -thymine [PMDTT]. be effective against the 1918 pandemic influenza A and this protective effect was accompanied. the families of the flaviviridae (i. to bind to the target cell receptor. Zanamivir. thus preventing their further spread to This error catastrophe has been shown only with polio- other host cells. which must be taken by ably mediated. 8:552–560 . in theory. the predominant mechanism by which ribavirin reduction in illness in 1–2 days. which contains a animal models as well as in humans (in the latter case. 3-deazaneplanocin A was found to protect block influenza A and B viruses. bunyaviridae (i. or target cellular proteins [54]. Machupo. there is no evidence of A. Junin. Ribavirin has only weak activity therapy [53. Also. The compounds that are currently under against flaviviruses.e. viral replicative cycle has been completed [37. When used therapeutically. by an enhanced production of IFN in (oral) inhalation. Figure 1) on the conjugation of phosphorodiamidate morpholino [56] have been described as potent and selective anti- oligomers with arginine-rich peptides to increase their HIV agents. Human immunodeficiency virus infections narito and Sabia). it has not been demonstrated with other RNA viruses such as HIV or HCV. Galanthus nivalis agglutinin and Hippeastrum hybrid agglutinin) represent potential candidate anti-HIV micro- For arenaviruses and bunyaviruses.sciencedirect. ribavirin.

irrespective of whether or not they are currently amen. De Clercq E. 2005. toxi. R-278474 highlights the important require. a novel class of herpesvirus antiviral agents. Hendrix M. 4-oxo-dihydroquinolines. Kibler P. Biochem Pharmacol 2004. Faucher AM. Coen DM: Identification of a small molecule able to antiviral therapy. 191:396-399. 77:1868-1876. Hewlett G. both present and future. 30:115-133. Betz UA. Eckenberg P. 11. De Clercq E: Efficacy of cidofovir in a murine model of disseminated progressive I am grateful to Christiane Callebaut for her invaluable editorial assistance. high oral bioavail- 9. Current Opinion in Microbiology 2005. 67:325-336. Brideau RJ. De Clercq E: Highly potent and selective inhibition of varicella- zoster virus replication by bicyclic furo[2. Hargrave KD. antiviral strategies for the management of cytomegalovirus DNA polymerases confer resistance to SARS. Neyts J: Therapeutic potential of nucleoside/ are also reviewed. including therapy. McGuigan C. Hendrix M. Rev Med Virol 2004. minimal side Schneider U. the  of special interest  of outstanding interest virus acquires resistance mutations in the gp120 glyco- protein that are predominantly located at the N-glycosy- 1. Hostetler KY. Thomsen DR. Possible strategies for the prevention and treatment of Bousseau A. Neyts J. De Bolle L. Ciesla SL. Beadle JR. of HHV-6 potential of oral cidofovir prodrugs for the prophylaxis infections. crystallographers. Kleymann G. which shows activity 6. De Clercq E: Antiviral drugs in current clinical use. adefovir. Bender W. Antimicrob Agents Chemother 2002. De Clercq E. molecular modellers. Andrei G. of DNA virus and retrovirus infections. Snoeck R. developed for the treatment of HIV infections (AIDS) 15. selective hemorrhagic fever virus infections are identified.com . others [60]. Antimicrob Agents Chemother virologists. De Clercq E: Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. 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is required to re-use any materials in Trends or Current Opinion journals or any other works published by Elsevier. 78:10617-10627. Paul J Am Chem Soc 2005. Princen K.: A induces massively increased interferon-a production in Mannose-specific plant lectins from the Amaryllidaceae Ebola virus-infected mice. 362:1953-1958. Balzarini J. Geisbert TW. Daeyaert F. Egberink H. of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 2003. Paul Janssen. Antimicrob Agents 52. Mol Pharmacol 55.  Busson R. De Clercq E. 127:5056-5065. phosphonates. Elsevier authors can obtain permission by completing the online form available through the Copyright Information section of Elsevier’s Author Gateway at http://authors.6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile 56. Froeyen M. 53. pressure by the mannose-specific plant lectins of Hippeastrum hybrid and Galanthus nivalis. Huggins JW: Treatment of lethal Ebola virus Deoxyribonucleoside (as well as ribonucleoside) phosphonates might infection in mice with a single dose of an S-adenosyl-L. Scroll down to the thumbnail of the required figure 4. de Jonge M. Janssen. Naesens L. Antiviral Res 2002. Vermeire K. Andrei G. Wang J. Locate the article with the required figure in the ScienceDirect journal collection 2. Balzarini J. Larsen T. Driscoll J. (R278474. 5. De Clercq E. Bolmstedt A. Vlasuk GP: Treatment of Ebola virus infection with a recombinant inhibitor 58. discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2. 45:135-147. Ying Y. 48:3858-3870. family qualify as efficient microbicides for prevention of human immunodeficiency virus infection. Place the cursor over the image and click to engage the ‘Enlarge Image’ option. (as well as HCV) infections. Current Opinion in Microbiology 2005. Paragas J. Open a blank slide in PowerPoint or other image-display program 7.4. Baker RO: 3-Deazaneplanocin De Clercq E. On a PC. Chemother 2004. Geisbert T.elsevier. Leyssen P. rilpivirine). Neyts J. Balzarini J. De Clercq E: New approaches toward anti-HIV chemotherapy. Alternatively. Right-click over the slide and select ‘paste’ (Mac users hit ‘Apple-V’ or select the ‘Edit-Paste’ pull-down option) Permission of the publisher. 8:552–560 www. What’s new in the anti-HIV chemotherapy field? An updated review on 59. Reuse of Current Opinion and Trends journal figures in multimedia presentations It’s easy to incorporate figures published in Trends or Current Opinion journals into your PowerPoint presentations or other image-display programs. Schols D: Marked 54. Van Laethem K. Froeyen M. Simply follow the steps below to augment your presentations or teaching materials with our fine figures! 1.com/. Herdewijn P: Deoxythreosyl Representative example of the unabated medicinal chemistry approach phosphonate nucleosides as selective anti-HIV agents. Pasquier E et al. Janssen PA. Peumans W. current anti-HIV drugs. Hatse S. represent a new approach for the therapy of HIV and hepatitis B virus homocysteine hydrolase inhibitor. Vermeire K. Bray M. Schols D: Profile of resistance of human immunodeficiency virus to mannose-specific plant lectins. Heeres J.: In search of diaminopyrimidines. 48:1901-1909. Rote WE. readers can access the request form through Elsevier’s main web site at http://www. Hensley LE. 57. Guillemont J. Lewi PJ. Peumans W et al. Perno C-F. Antiviral Res 2000. Pannecouque C. 67:1556-1565. 48:1297-1313.elsevier. Aquaro S. Vanden Mooter G.sciencedirect.: Antiviral potential of a new generation of acyclic nucleoside 60. Hatse S. 2005. Hocková D et al. Van Laethem K. De Clercq E: Emerging anti-HIV drugs. Jahrling PB. Young HA. Van Damme E. Vinkers M.com/ locate/permissions.560 Antimicrobials 50. the 6-[2-(phosphonomethoxy)alkoxy]-2. De Clercq E. Peumans W. Nucleosides Nucleotides Nucleic Acids a novel anti-HIV drug: multidisciplinary coordination in the 2005. Kempeneers V. in press.  Koymans L. Balzarini J. Wu T. Click on the ‘Full text + links’ hyperlink 3. towards the development of the ‘cure’ for AIDS: the legacy of Dr. Fredeking TM. Expert Opin Emerg Drugs depletion of glycosylation sites in HIV-1 gp120 under selection 2005. Bolmstedt A.com . Bray M. Arnold E. J Virol 2004. Geisbert JB. as a tribute to the late Dr. J Med Chem 2005. Snoeck R. Van Damme E. De Clercq E. Raymond JL. 55:151-159. Vandamme A-M. Elsevier. 51. Hatse S. 10:241-274.  J Med Chem 2005. Pannecouque C. right-click over the expanded image and select ‘Copy’ from pull-down menu (Mac users: hold left button down and then select the ‘Copy image’ option) 6.