C-Nucleosides To Be Revisited - Journal of Medicinal Chemistry (ACS

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C‑Nucleosides To Be Revisited Miniperspective Erik De Clercq*

J. Med. Chem. 2016.59:2301-2311. Downloaded from pubs.acs.org by WASHINGTON UNIV on 09/19/18. For personal use only.

Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium ABSTRACT: Two new C-nucleoside analogues, BCX4430, an imino-C-nucleoside, and GS-6620, a phosphoramidate derivative of 1′-cyano-2′-C-methyl-4-aza-7,9dideazaadenosine C-nucleoside, have been recently described as effective against filovirus infections (Marburg) and hepatitis C virus (HCV), respectively. The first C-nucleoside analogues were described about half a century ago. The C-nucleoside pseudouridine is a natural component of RNA, and various other C-nucleoside analogues have been reported previously for their antiviral and/or anticancer potential, the most prominent being pyrazofurin, tiazofurin, and selenazofurin. In the meantime, showdomycin, formycin, and various triazole, pyrazine, pyridine, dihydroxyphenyl, thienopyrimidine, pyrazolotriazine, and porphyrin C-nucleoside analogues have been described. It would be worth revisiting these C-nucleosides and derivatives thereof, including their phosphoramidates, for their therapeutic potential in the treatment of virus infections and, where appropriate, cancer as well. obtained for compound 12 and compound 2,3 reinforce the concept that the C-nucleosides should be revisited, at least for their antiviral (and eventually also their antitumoral) activity. A comprehensive description of the chemical synthesis of new nucleoside analogues, including changes in the heterocyclic base,

1. INTRODUCTION All nucleoside analogues that have been licensed for clinical use and finally commercialized belong to the classical nucleoside analogues. This means that their heterocyclic moiety (mostly purine or pyrimidine) is linked to their sugar part (mostly ribose or 2-deoxyribose) through (the purine or pyrimidine) nitrogen. They could therefore be called N-nucleosides. All the nucleosides momentarily on the market are N-nucleosides. The best known C-nucleoside is pyrazofurin, which, despite the fact that it was first mentioned in 1975,1 now 40 years ago, was never commercialized as either anticancer or antiviral agent. Yet C-nucleosides offer a distinct advantage over the canonical N-nucleosides in that they are resistant against degradation by phosphorolysis by phosphorylases which otherwise would cleave the N-glycosidic linkage. The advent of two new C-nucleosides, the first one being the imino-C-nucleoside BCX4430 (1) as a potential therapeutic for the treatment of Ebola virus (EBOV) infections,2 and the second, GS-6620 (2), a C-nucleoside phosphoramidate prodrug containing the characteristic 2′-C-methyl function, which may offer considerable potential for the treatment of hepatitis C virus (HCV) infections,3 has heralded renewed interest in the potential usefulness of C-nucleosides as antiviral agents. What seems essential for antiviral activity is that these C-nucleosides contain either an aminoaza function, as in adenine, or carboxamido (or -imido) function, as in ribavirin and favipiravir, for broad-spectrum antiviral activity (including filoviruses) or, as in compound 2, a 2′-C-methyl group that is specific for anti-HCV activity. Many more variations could now be implemented in the chemical structure of C-nucleosides that could improve their efficacy and/or safety profile, and/or enlarge their activity spectrum, and new prodrugs could be envisaged, which were not yet possible when the C-nucleoside pyrazofurin was first described. These considerations, together with the promising results already © 2015 American Chemical Society

Figure 1. Pseudouridine and pseudoisocytidine. Received: July 23, 2015 Published: October 29, 2015 2301

DOI: 10.1021/acs.jmedchem.5b01157 J. Med. Chem. 2016, 59, 2301−2311

Journal of Medicinal Chemistry

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pseudouridine 5′-phosphate glycosidases.5 Pseudouridine is present in all structural RNAs, and for instance, the mammalian ribosomal RNA contains ∼100 pseudouridines per ribosome.6 The N5-hydrogen may act as an additional hydrogen bond donor, thus contributing to the stabilization of higher order RNA structures.7 Pseudoisocytidine (PIC), also previously referred to as ψICyd, has been developed as a candidate antileukemic compound because it is neither subject to enzymatic cleavage of the glycosidic bond nor susceptible to enzymatic deamination.8 PIC occurs as two isomers, H3 isomer (4) and H1 isomer (5) (Figure 2).8 It has since long been known for its antileukemic effects;9 it was originally shown to be active against 1-β-D-arabinofuranosylcytosine (ara-C)-resistant mouse leukemia cell lines. Pseudoisocytidine could be incorporated into both DNA and RNA,10 and this incorporation may be a prerequisite for its therapeutic activity, i.e., in the treatment of P815 leukemia.11 However, in phase I clinical evaluation, pseudoisocytidine was shown to be hepatotoxic,12 and this adverse event must have ended the career of pseudoisocytidine (4, 5) as a potential antileukemic drug.

Figure 2. Pyrazofurin and hypothetical pyrazofurin derivatives.

replacement of the furanose ring by a different carbo- or heterocyclic ring, and the preparation of C-nucleosides, is provided by Pedro Merino.4

2. PSEUDOURIDINE AND PSEUDOISOCYTIDINE Pseudouridine (3) (Figure 1) is a noncanonical C-nucleoside commonly present in RNA, which is not metabolized in mammals but can be recycled by a unique set of bacterial

Figure 3. Favipiravir (T-705) and hypothetical C-nucleoside derivatives from favipiravir (RMP = ribosyl monophosphate; RTP = ribosyl triphosphate). 2302



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Figure 4. Tiazofurin, selenazofurin, and structurally related C-nucleoside analogues.

decarboxylase,19 which meant that compound 6 had to be phosphorylated to its monophosphate (by adenosine kinase rather than uridine kinase): consequently, hepatoma cells deficient in adenosine kinase developed resistance in their proliferation to pyrazofurin.20 In fact, orotate phosphoribosyl transferase and OMP decarboxylase are two enzymatic functions of the same enzyme, termed UMP synthase,21−23 and thus 6 5′-monophosphate was assumed to target the “multienzyme” UMP synthase. Although the in vitro inhibition of Plasmodium falciparum, as the consequence of the inhibitory effect of 6 on de novo pyrimidine biosynthesis, was already mentioned in 1986,24 the potential of 6 for the treatment of parasitic infections would only receive renewed attention 20 years later, when Langley et al.25 re-emphasized the role OMP decarboxylase as a therapeutic target for chemotherapeutic intervention for P. falciparum infections. P. falciparum is responsible for most of the 500 million cases of malaria worldwide and for 2−3 million annual deaths.26 The importance of a relatively simple C-nucleoside such as compound 6, which in addition could be readily chemically modified (Figure 2) in the potential treatment of a plague such as malaria, could never be underestimated.

3. PYRAZOFURIN (6): ORIGINALLY PURSUED AS AN ANTICANCER AGENT Compound 6 (3-β-D-ribofuranosyl-4-hydroxypyrazole-5-carboxamide, previously designated “pyrazomycin”) (Figure 2) was isolated from the broth filtrate of Streptomyces candidus, along with two other compounds, pyrazomycin B (the α-anomer) (7) and oxazinomycin (minimycin) (8).1 Gutowski et al.1 reported that the α- and β-anomers of pyrazofurin were readily interconvertible under surprisingly mild conditions. The α-anomer of pyrazofurin,13,14 as is the rule for α-nucleosides in general, would possess little or no biological activity. Although compound 6 was originally shown to exhibit both antiviral properties (i.e., against Friend leukemia virus) and antitumor properties (i.e., against DMBA (9,10-dimethyl-1,2benzanthracene)-induced mammary carcinoma), 1 it was primarily pursued for its antitumor potential. Compound 6 was shown to inhibit the growth of some transplantable tumors in mice and rats15 and to inhibit Novikoff rat hepatoma cells and other cell lines,16 apparently due to the inhibition of de novo biosynthesis of pyrimidine nucleosides,17 which was later attributed to the inhibitory effect of pyrazofurin monophosphate on the conversion of OMP to UMP.17,18 The principal target of action was identified as the OMP 2303



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Figure 5. Imino-C-nucleoside analogues: compound 1 and Imm-H.

4. COMPOUND 6, AN UNSONG ANTIVIRAL C-NUCLEOSIDE Among the antivirally active nucleoside analogues that have (so far) been licensed for clinical use, none is a C-nucleoside. Yet, 6 could be viewed as one of the archetype broad-spectrum antiviral agents, with an antiviral potency exceeding by far that of ribavirin (9).27 Prominent in the activity of 6 was its exquisite potency against vesicular stomatitis virus (VSV), which back in 1978 already heralded its potential usefulness in the treatment of Ebola virus (EBOV)28 that in 1977 had first been identified.29 However, compound 930 was from the 1970s onward considered as the broad-spectrum antiviral nucleoside of the future, and this role was fulfilled when from the 2000s 9 became the standard of care (SOC), when combined with pegylated interferon, for the treatment of hepatitis C virus (HCV) infections. Yet, 6 should not have been neglected and not only because of its exquisite potency against VSV and other RNA viruses [picorna (polio, Coxsackie), paramyxo (measles), and toga (Sindbis)];27 this list was later extended to Rift Valley fever, Venezuelan equine encephalomyelitis, Sandfly, Pichinde, and Lassa virus.31 Equally remarkable was the exquisite potency of 6 against Gross murine leukemia virus replication32 and vaccinia virus replication, which could be considered as a paradigm for the chemotherapy of poxviruses at large.33 Over a period of 2 decades (1980−2000), 6 would further be shown effective against rotavirus replication,34 respiratory syncytial virus (RSV) replication,35 measles [subacute sclerosing panencephalitis (SSPE)] virus replication,36 arenavirus (Junin, Tacaribe) replication,37 infectious pancreatic necrosis virus (IPNV, a member of the birnaviridae that could cause severe infections in trout and salmon farms),38 and West Nile virus.39 For Sindbis virus, three mutations (M287L, K592I, and P609T)

have been identified in the RNA polymerase of virus resistant to 6.40 These mutations increase the affinity of the RNA polymerase for CTP and UTP40 and could readily be explained by the mode of action of 6, which, if targeted at the OMP decarboxylase, would decrease the levels of CTP and UTP in the cells exposed to 6. It is curious that 6, although it has been known for ∼40 years (since Gutowski reported it first in Ann. N. Y. Acad. Sci.1), was never seriously considered or developed for either anticancer or antiviral activity. The emergence of the recent Ebola virus epidemic may represent an important stimulus in this direction, since 6 is highly active against VSV, which could be considered as a surrogate virus for EBOV.28 It is also noteworthy that 6 shares a carboxamide function with two N-nucleoside analogues [or can be converted to the metabolites thereof, 9 and favipiravir (T-705) (10)]. For 9, C-nucleosides, i.e., tiazofurin and selenazofurin, have been synthesized (see section 5), but for 10, which incidentally has proven effective against a broad spectrum of RNA viruses (including EBOV),28,41 the C-nucleoside counterparts have not (yet) been reported. Some hypothetical C-nucleoside derivatives of 10 are suggested (Figure 3). Compound 10 is assumed to be converted intracellularly to T-705 ribosyltriphosphate (RTP) (13) after T-705 is first converted to T-705 ribosylmonophosphate (RMP) (12).41

5. TIAZOFURIN (14), SELENAZOFURIN (15), AND STRUCTURALLY RELATED C-NUCLEOSIDE ANALOGUES The first synthesis of compound 14 (Figure 4) was reported by Roland Robins and his co-workers in 1977.42 Kini et al.43 reported the synthesis of aza-thiafurin, actually an iminoC-nucleoside (Figure 4), and Chiacchio et al.44 synthesized an enantiomerically pure isoxazolidinyl derivative of 14. Compound 14 was found to inhibit the growth of several tumors, including 2304



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Figure 6. C-nucleosides active against HCV leading to compound 2.

as pleuropericarditis and a general illness best described as a “viral-like” syndrome noted during the phase I clinical evaluation of 1456 must have compromised its further development as an anticancer drug. Compounds 14 and 15 were never considered as potential antiviral drugs, although they showed synergistic antiviral effects with ribavirin.57 Several structural analogues of 14, i.e., furanfurin and thiophenfurin58 and imidazofurin59 (Figure 4), were synthesized, and some of these C-nucleosides (i.e., furanfurin) could even be considered as ligands to A1 adenosine receptors.60 C-nucleoside derivatives, such as 14 and 15 and their “imino” counterparts (i.e., iminotiazofurin (16)) (Figure 4), should be revisited for their antiviral and/or anticancer potential.

Lewis lung carcinoma, which is refractory to most antitumor agents.45 Apparently, tiazofurin was phosphorylated to its 5′-monophosphate and then anabolized to an analogue of NAD, namely, TAD (thiazole-4-carboxamide adenine dinucleotide), which inhibited IMP dehydrogenase, with subsequent depletion of GMP, GDP, and GTP.46−49 Compound 14 treatment caused significant antitumor activity in rats inoculated with hepatoma 3924A50 and was found to act synergistically with quercetin in their cytotoxicity against ovarian carcinoma cells.51 Following 14, selenazofurin (15) (Figure 4) was synthesized,52 and SAD (selenazofurin adenine dinucleotide), like TAD, was found to inhibit the NAD interaction with IMP dehydrogenase, as well as poly(ADP-ribose) metabolism.53 A third compound, benzamide riboside, 3-(1-deoxy-β-Dribofuranosyl)benzamide, was likewise shown to be a potent inhibitor of IMP dehydrogenase, depleting the guanylate pools.54 Compound 14 proceeded to phase II clinical trials in patients with chronic myelogenous leukemia.55 The toxic side effects such

6. IMINO-C-NUCLEOSIDE ANALOGUES: BCX4430 (1) AND IMMUCILLIN H (IMM-H) (17) Antiviral activity for imino-C-nucleoside analogues61 had never been reported. Therefore, the announcement of the protective 2305



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effect of the C-nucleoside 1 against a filovirus infection (Marburg) in cynomolgus macaques came as a total surprise.2 This imino-Cnucleoside would be rapidly phosphorylated to its triphosphate (Figure 5) and then inhibit the viral RNA polymerase through nonobligate RNA chain termination.2 But being an adenosine analogue, why was compound 1 not considered as a potential S-adenosylhomocysteine hydrolase (SAH) inhibitor? This mode of action would not require any metabolism (i.e., phosphorylation). Compound 1 was reported as being effective against both (−)RNA and (+)RNA viruses2 [although the picornaviridae were erroneously labeled as (−) instead of (+)RNA viruses, and the (−)RNA rhabdoviridae (rabies, vesicular stomatitis virus) were not included among the viruses tested]. In a separate study, compound 1 was found effective in the treatment of yellow fever virus, a (+)RNA flavivirus, in a hamster model.62 The question that could be raised for 1, however, is whether it would be sensitive to deamination, i.e., by adenosine deaminase. For vidarabine (ara-A, arabinosyladenine) this deamination results in the formation of the antivirally inactive arabinosylhypoxanthine (ara-Hx). For 1, it leads to compound 17 (Figure 5).63,64 Compound 17 is a powerful transition-state analogue inhibitor of purine nucleoside phosphorylase (PNP) (Figure 5), which selectively inhibits the proliferation of human T-lymphocytes.65 This may suggest clinical potential for 17 in the treatment of human T-cell leukemia and lymphoma and other diseases characterized by activated T cell responses, such as autoimmunity, organ transplantation, and graft-versus-host disease.65

7. C-NUCLEOSIDE HCV POLYMERASE INHIBITOR GS-6620 (2) Foremost of the nucleoside analogues that have entered clinical trials for the treatment of HCV infections are N-nucleosides containing a 2′-C-Me branched sugar; one of these compounds (sofosbuvir) is already on the market, while another (mericitabine) is still in clinical development. Therefore, the first C-nucleoside HCV polymerase inhibitor 2, shown to demonstrate antiviral effectiveness in HCV-infected patients, received due attention.3 As the starting point for the synthesis of 2, the 1′-cyano4-aza-7,9-diazaadenosine C-nucleoside (Figure 6) could be conceived, which was shown to be effective against a broad range of viruses, including HCV, yellow fever virus, Dengue virus, parainfluenza virus, and SARS coronavirus.66 As predecessor of this compound, 4-aza-7,9-diazaadenosine C-nucleoside (19) (Figure 6) could be considered,67 which itself could be viewed as derived from the naturally occurring, but rather cytotoxic N-nucleoside, tubercidin (7-deazaadenosine) (18) (Figure 6).68,69 Butora et al.70 then demonstrated that the C-nucleoside scaffold could be tolerated for HCV inhibitory activity, as exemplified specifically for 9-deaza- and 7,9-dideaza-7-oxa-2′-C-methyladenosine (Figure 6).71 The synthesis of the 1′-cyano-2′-C-methyl-Cnucleoside parent (20, 23) (Figure 6) of 2 was described by Mish et al.72 In fact, various derivatives of imidazotriazine and pyrrolotriazine C-nucleosides were described as potential new anti-HCV agents by Draffan et al.,73 and one, the 7-carboxamido derivative (21) (Figure 6) drew particular attention because of its extremely potent activity (EC50 = 0.006 μM) against HCV. This (carbox)amido group could be involved in hydrogen bonding during base pairing. Various prodrugs of imidazotriazine and pyrrolotriazine C-nucleosides have in the meantime been synthesized,74 but in this study, the 7-carboxamido derivative was not included. C-nucleosides, such as 2′-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (22), may offer considerable potential for the treatment of HCV infections provided a sufficient therapeutic

Figure 7. Triazolyl, pyrazinyl, benzamide, pyridinyl, phenyl, iodobenzyl, and tetrafluoroaryl C-nucleoside analogues.

margin can be established.75 This goal may be achieved by creating the appropriate prodrug(s), as has been attempted by the design of 2 (Figure 6).3,76,77 The favorable preclinical characteristics make 2 a suitable clinical candidate, but further optimization of drug delivery may seem required for future clinical development.78 2306



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Figure 8. Showdomycin, L-showdomycin, formycin, carbocyclic 4′-epiformycin, thieno[3,4-d]pyrimidine 2′,3′-dideoxy-, pyrazolo[1,5-a]-1,3,5-triazine2′-deoxy-, and porphyrin 2′-deoxy-C-nucleoside analogues, and the amphipathic fusion inhibitor dUY11.

8. TRIAZOLE, PYRAZINE, BENZAMIDE, PYRIDINE, DIHYDROPHENYL, IODOBENZYL, AND TETRAFLUOROARYL C-NUCLEOSIDES

of OMP decarboxylase, noteworthy, again, in the presence of a carboxamido entity in the structure.79 Certain pyrazine (1,4-diazine) C-nucleosides, i.e., ethyl 3,5-dichloro-6-(β-D-ribofuranosyl)pyrazine-2-carboxylate (25) (Figure 7), were reported to be antivirally active [i.e., against cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1)],80 but their antiviral properties against

3-β-Ribofuranosyl-1,2,4-triazole-5-carboxamide C-nucleosides (24) (Figure 7) have been found to induce differentiation of the human myeloid leukemia cell line K562, through inhibition 2307



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proved effective against enveloped viruses,102 which in principle also encompass the filoviruses (including EBOV).

other viruses were not assessed nor was the antiviral activity of other pyrazine C-nucleosides. The benzamide C-nucleoside (26) (Figure 7), as already mentioned, showed potent antiproliferative activity through the formation of its NAD analogue that inhibited the NAD-dependent IMP dehydrogenase.81,82 Both 6-substituted pyridin-2-yl and 6-substituted pyridin-3-yl C-nucleosides (27)83,84 have been synthesized with biologic properties that remain to be characterized (Figure 7). The 2′,3′-dideoxy-C-nucleoside, dd2APy (28) (Figure 7) has been identified as an HIV reverse transcriptase chain terminator,85 whereas a variety of 5′-triphosphates of β-Cnucleosides carrying an aromatic nucleobase such as 2-, 3-, or 4-hydroxyphenyl or phenyl or 3,4-dihydroxyphenyl group (29) (Figure 7) could serve as inhibitors of DNA polymerase reactions.86 Kool and co-workers87,88 synthesized nonpolar hydrophobic isosteres of pyrimidine nucleosides (i.e., thymidine): the 5-IDFPdR 2′-deoxy-C-nucleoside (30) (Figure 7) was aimed at increasing the stability toward phosphorolysis by pyrimidine phosphorylase, increasing lipophilicity and ability to cross the blood−brain barrier, and increasing resistance toward catabolism and deiodination.89 Tetrafluorinated-C-nucleosides (i.e., 3,3,4,4-tetrafluoroaryl-Cnucleoside analogues) (31) (Figure 7) were synthesized by Bonnac et al.,90 but their therapeutic potential, if any, remains to be assessed. Also, various pyridine, pyrimidine, and pyridinone C-nucleoside phosphoramidates for probing cytosine function in RNA have been synthesized,91 and the synthesis of phenyl-, bisphenyl-, or phenylcyclohexyl-C-nucleoside analogues was aimed at probing the genetic alphabet in the center of a DNA duplex.92

10. CONCLUSIONS Although a variety of C-nucleoside analogues have been described as anticancer and/or antiviral agents, none have ever been developed as an anticancer or antiviral drug. The advent of the imino-C-nucleoside 1 for the treatment of EBOV, Marburg, and other virus infections, such as yellow fever, and of 2, a phosphoramidate prodrug of a C-nucleoside containing the characteristic 2′-C-methyl entity, for the treatment of HCV infections indicates that it may be worth revisiting C-nucleosides for their anticancer and/or antiviral potential. This may require further chemical modifications by introduction of the appropriate substituents or derivatization to their protides (i.e., phosphoramidate prodrugs). Foremost of the “old” C-nucleosides that should be revisited is 6, which once upon a time (40 years ago) was found to be exquisitely potent against vesicular stomatitis virus, a surrogate for EBOV, and murine leukemia virus but which ever since has been largely ignored, if not forgotten. Similarly, the C-nucleosides 14 and 15 should deserve renewed attention, and so should 32 and 34 and the new triazole, pyrazine, pyridine, thienopyrimidine, pyrazolotriazine, and porphyrin C-nucleosides that in the meantime have been synthesized. Also, the possibility of synthesizing C-nucleosides, starting from 10, a broadspectrum anti-RNA viral agent (that is also active against EBOV), should be entertained. Akin to 2, derivatization of these C-nucleosides whether “old” or “new” to their phosphoramidate prodrugs should be envisaged.

9. SHOWDOMYCIN (32), L-SHOWDOMYCIN (33), FORMYCIN (34), CARBOCYCLIC 4′-EPIFORMYCIN (35), THIENO[3,4-D]PYRIMIDINE (36), PYRAZOLO[1,5-A]-1,3,5-TRIAZINE (37), AND PORPHYRIN (38) C-NUCLEOSIDES Compound 32, a C-nucleoside antibiotic, was once upon a time considered as “an approach to selective cancer chemotherapy”,93 due to its reactive moiety, maleimide, an alkylating agent (Figure 8).94 A versatile enantioselective strategy then led to the synthesis of 33 (Figure 8),95 but whether (and how) this versatile route to the preparation of biologically interesting C-nucleosides is still unsettled. Equally unsettled is the possible future of the C-nucleoside 34, which together with other nucleoside antibiotics, tubercidin, toyocamycin, and sangivamycin, I described back in 198768 (Figure 8). Formycin, a C-nucleoside analogue of inosine is by itself rather cytotoxic68 but useful to measure facilitated nucleoside transport in mammalian cells.96 The carbocyclic derivative, 35 (Figure 8) may be worth further pursuing as a source for further chemical modifications, although by itself, carbocyclic 4′-epiformycin is devoid of any antiviral potential.97 Likewise, 36 (Figure 8) has been synthesized, but again, these C-nucleoside analogues did not show antiviral activity (against HIV).98 Compound 37 was synthesized as a deoxyadenosine analogue (Figure 8) that was more resistant to acid-catalyzed hydrolysis than dA, yet able to base-pair with 2′-deoxythymidine.99 Whether it would possess any antitumor and/or antiviral properties was not explored. A number of mono- and diindole C-nucleoside analogues have been synthesized,100 but again, their biological properties were not assessed. Intriguing is compound 38 (Figure 8) synthesized by Morales-Rojas and Kool;101 this compound could be incorporated into DNA. But more important is that structurally, this compound is reminiscent of the amphipathic fusion inhibitors (i.e., dUY11), which have

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 3216337367. Notes

The authors declare no competing financial interest. Biography Erik De Clercq, since 2007 (until present), has been teaching the course of “Chemistry at the Service of Medicine” at the Faculty of Sciences at the University of South Bohemia (Č eske Budĕjovice, Czech Republic) in a joint program with Keppler University (Linz, Austria). He received in 2010 jointly with Dr. Anthony S. Fauci the Dr. Paul Janssen Award for Biomedical Research. He has (co)discovered a number of antiviral drugs currently used in the treatment of HSV infections (valaciclovir), VZV (brivudin), CMV (cidofovir), HBV [adefovir dipivoxil and tenofovir disoproxil fumarate, Viread (TDF)], and HIV infections (TDF). The combination of TDF with emtricitabine (Truvada) was approved by the U.S. FDA in 2012 for the prophylaxis of HIV infections.

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ACKNOWLEDGMENTS

I thank Christiane Callebaut for her proficient editorial assistance. This paper is dedicated to my friends, the chemists who played a pioneering role in the synthesis of C-nucleosides: C. K. (“David”) Chu, Choung Kim, Roland K. Robins (memory), Leroy B. Townsend, and Kyo Watanabe (memory).

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ABBREVIATIONS USED CMV, cytomegalovirus; EBOV, Ebola virus; HCV, hepatitis C virus; HSV-1, herpes simplex virus type 1; VSV, vesicular stomatitis virus 2308



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