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Review

Approved Antiviral Drugs over the Past 50 Years

Erik De Clercq, Guangdi Li
Erik De Clercq
aKU Leuven-University of Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium
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  • For correspondence: erik.declercq@kuleuven.be liguangdi.research@gmail.com
Guangdi Li
aKU Leuven-University of Leuven, Rega Institute for Medical Research, Department of Microbiology and Immunology, Leuven, Belgium
bDepartment of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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  • For correspondence: erik.declercq@kuleuven.be liguangdi.research@gmail.com
DOI: 10.1128/CMR.00102-15
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  • FIG 1
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    FIG 1

    History of antiviral drugs approved between January 1959 and April 2016. (A) Approved antiviral drugs visualized in the zodiac. The gray arrow shows the dates of approval of antiviral drugs from January 1959 to April 2016. Twelve signs are positioned in a circle. Each sign indicates a drug group whose name is annotated outside the circle. In the drug group, each red star within a sign represents an approved drug, placed according to the year of approval. Yellow stars indicate approved drugs that have been discontinued or abandoned for clinical use. A total of 90 stars thus represent all approved antiviral drugs, and each drug star is positioned according to its approval date (Table 2). In this picture, every approved drug could be conceived as a “superstar,” and its contribution to human health is worthy of being remembered and respected. Therefore, this zodiac-based figure metaphorically recognizes each antiviral drug as a star in the universe, commemorating the significant contributions of antiviral drug discovery and development over the past 50 years. A list of drug abbreviations is available in Table 2. Movies and label information for approved drugs are accessible online (see http://www.virusface.com/). (B) Timeline of approval of drugs against 9 human infectious diseases (HIV, HBV, HCV, HSV, HCMV, HPV, RSV, VZV, and influenza virus). The x axis indicates the period from January 1959 to April 2016, and the y axis shows the total number of approved drugs. For each virus, a colored line demonstrates the total number of approved drugs. Moreover, years of discovery of HBV (1963), HPV (1965), HIV (1983), and HCV (1989) are indicated, while the other five viruses were discovered before 1959 (Table 1).

  • FIG 2
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    FIG 2

    Virus family, morphology, and transmission of HIV, HBV, HCV, HSV, HCMV, HPV, RSV, VZV, and influenza virus. Nine human viruses are classified into DNA viruses (HBV, HCMV, HSV, HPV, and VZV), RNA viruses (HCV, RSV, and influenza virus), and retroviruses (HIV). These viruses are from 7 families: the Hepadnaviridae (HBV), the Papillomaviridae (HPV), the Herpesviridae (HCMV, HSV, and VZV), the Flaviviridae (HCV), the Paramyxoviridae (RSV), the Orthomyxoviridae (influenza virus), and the Retroviridae (HIV). Schematic views and electron micrograph images of viral particles are illustrated in boxes, where particle sizes measured as diameters and viral genome types (circular/linear dsDNA or linear RNA) are also indicated (Table 1). Human viruses are further characterized with the possible animal reservoirs. HIV is known to be transmitted from chimpanzees (HIV-1 groups M and N), gorillas (HIV-1 groups P and O), or sooty mangabeys (HIV-2) (11, 14, 15). Influenza viruses that infect humans originate mostly from birds, pigs, or seals (36, 401). Although the origin of HBV has yet to be clarified, bats might be a potential reservoir for HBV (47). HPV has been widely found in birds, reptiles, marsupials, and mammals, but cross-transfer between species is rare (54). Four human viruses (RSV [41], HCMV [64], HSV [74], and VZV [80]) circulate only in human populations and do not have any animal reservoir. In addition, it remains unclear whether HCV has any animal reservoir (27, 476). (The HCV electron micrograph image is republished from reference 20 with permission of the publisher. The HPV electron micrograph image was obtained from the Laboratory of Tumor Virus Biology at the National Cancer Institute [https://visualsonline.cancer.gov/]. The electron micrograph images for HBV, HCMV [by Sylvia Whitfield], HSV [by Fred Murphy and Sylvia Whitfield], VZV [by Erskine L. Palmer and B. G. Partin], RSV [by Erskine L. Palmer], influenza virus [by Erskine L. Palmer and M. L. Martin], and HIV [by Maureen Metcalfe and Tom Hodge] were obtained from the Centers for Disease Control and Prevention [http://phil.cdc.gov/phil/home.asp].)

  • FIG 3
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    FIG 3

    Antiviral drug groups for the treatment of 9 infectious diseases. Approved antiviral drugs are grouped for RNA viruses (HCV, RSV, and influenza virus), DNA viruses (HCMV, HBV, HPV, HSV, and VZV), and retroviruses (HIV). Names of antiviral drugs that are currently in use are enclosed in orange oblongs. Names of discontinued or abandoned antiviral drugs are enclosed in gray oblongs. Those drugs that inhibit more than one virus are shown in the overlapping regions between virus groups. For HCV drugs, a plus symbol is used to indicate the approved combination drugs (simeprevir plus sofosbuvir, sofosbuvir plus daclatasvir, daclatasvir plus asunaprevir, and ribavirin plus PegIFNα-2b).

  • FIG 4
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    FIG 4

    Mechanisms of drug actions during the viral life cycle. Twelve drug groups ordered by roman numerals are shown at the bottom, and their drug actions that interfere with major stages of the viral life cycle are highlighted by red arrows. Solid black arrows indicate direct biological pathways involving viral replication, and dotted black arrows indicate biological pathways with intermediate pathways inside host cells. Major viral stages are illustrated, including endocytosis, exocytosis, virus entry, reverse transcription, virus integration, viral transcription, viral translation, virus budding/release, virus maturation, and other pathways associated with cellular compartments (Golgi apparatus, mitochondria, endoplasmic reticulum [ER], ribosome, proteasome, polysome, and endosome) (for more details, see references 177, 300, and 466). Notably, replication pathways of DNA viruses (HCMV, HBV, HPV, HSV, and VZV), RNA viruses (HCV, RSV, and influenza virus), and retroviruses (HIV) diverge after entering host cells. The RNA viruses replicate in the cytoplasm, but DNA viruses and retroviruses further intrude into the nucleus for their DNA synthesis. Note that drug group XIII is not displayed because drugs in this group act mainly as immunoregulatory or antimitotic agents, and they do not directly target viral proteins. Shapes and sizes of proteins and cellular components are not to scale.

  • FIG 5
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    FIG 5

    HCMV and HSV-1 DNA polymerase structures and chemical formulas of pyrophosphate analogues, 5-substituted 2′-deoxyuridine analogues, and nucleoside analogues. (A) Tertiary structures of HCMV DNA polymerase in complex with dsDNA and foscarnet (PDB accession number 3KD5). HCMV DNA polymerase is shown in pink. The dsDNA is placed in the center, where foscarnet inhibits DNA synthesis at the active site of HCMV DNA polymerase. Structural movies that demonstrate drug binding are available online (see http://www.virusface.com/). PyMOL V1.7 visualization software (http://www.pymol.org/) was used. (B) Tertiary structures of HSV-1 DNA polymerase complexed with dsDNA and ATP (PDB accession numbers 2GV9 and 4M3R). HSV-1 DNA polymerase is shown in pink. ATP near the catalytic site is displayed in the drug-binding pocket. The triphosphate form of approved antiviral inhibitors (e.g., vidarabine triphosphate) can compete with dATP to inhibit the replication activity of HSV DNA polymerase. (C) Chemical formula of foscarnet in the group of pyrophosphate analogues. (D to F) Chemical formulas of idoxuridine, trifluridine, and brivudine in the group of 5-substituted 2′-deoxyuridine analogues. (G to J) Chemical formulas of telbivudine, entecavir, vidarabine, and FV100 in the group of nucleoside analogues. Note that FV100 is an experimental inhibitor in phase 3 clinical trials.

  • FIG 6
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    FIG 6

    Tertiary structures of HIV-1 reverse transcriptase and chemical formulas of NRTIs and NNRTIs. (A) HIV-1 RT complexed with dsDNA and zidovudine triphosphate (left) (PDB accession number 3V4I) and nevirapine (right) (PDB accession number 4PUO). Two subunits of the HIV-1 RT heterodimer are shown in pink and orange, respectively. Zidovudine triphosphate targets the drug-binding pocket of NRTIs, known as the catalytic site, to inhibit the activity of HIV-1 RT during DNA synthesis. Nevirapine targets the drug-binding pocket of NNRTIs, known as the allosteric site, to block the activity of HIV-1 RT during DNA synthesis (see structural movies at http://www.virusface.com/). (B to H) Chemical formulas of zidovudine, stavudine, zalcitabine, emtricitabine, didanosine, lamivudine, and abacavir in the group of NRTIs. (I to M) Chemical formulas of delavirdine, nevirapine, efavirenz, rilpivirine, and etravirine in the group of NNRTIs.

  • FIG 7
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    FIG 7

    Tertiary structures of HIV-1 protease and chemical formulas of HIV protease inhibitors. (A) HIV-1 protease dimer complexed with lopinavir (PDB accession number 2Q5K). The side view (left) and top view (right) of structures are presented. (B to K) Chemical formulas of nelfinavir, saquinavir, indinavir, atazanavir, lopinavir, ritonavir, fosamprenavir, amprenavir, darunavir, and tipranavir in the group of protease inhibitors. (L) Chemical formula of cobicistat. Cobicistat is a pharmacoenhancer used with HIV protease inhibitors, but cobicistat alone shows no antiviral activity.

  • FIG 8
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    FIG 8

    Tertiary structures of HCV NS3/NS4B protease and chemical formulas of HCV protease inhibitors. (A) HCV NS3/NS4B protease in complex with simeprevir (PDB accession numbers 3KEE and 4B76). HCV NS3 and NS4B proteins are shown in pink and orange, respectively. (B to H) Chemical formulas of boceprevir, telaprevir, asunaprevir, simeprevir, paritaprevir, vaniprevir, and grazoprevir in the group of HCV protease inhibitors.

  • FIG 9
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    FIG 9

    Tertiary structures of viral integrase and chemical formulas of HIV integrase inhibitors. (A) Viral integrase of prototype foamy virus in complex with dsDNA and dolutegravir (PDB accession number 3S3N). A dimer structure of the viral integrase is shown in pink and cyan, respectively. Although the structure of HIV integrase in complex with its inhibitors is still lacking, approved antiviral inhibitors that target HIV and prototype foamy virus integrase are believed to share similar mechanisms (477). (B to D) Chemical formulas of raltegravir, elvitegravir, and dolutegravir in the group of HIV integrase inhibitors.

  • FIG 10
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    FIG 10

    Chemical formulas of HIV entry inhibitors and tertiary structures of CCR5, HIV-1 GP41, and RSV glycoprotein F. (A) Chemical formula of docosanol. (B and C) Chemical formula of maraviroc and the CCR5 coreceptor in complex with maraviroc (PDB accession number 4MBS). The top and side views of the CCR5 structure are presented. (D and E) Chemical formula of enfuvirtide and tertiary structure of the HIV-1 GP41 trimer (PDB accession number 2X7R). Enfuvirtide is derived from the green region of HIV-1 GP41. The top and side views of the HIV-1 GP41 trimer are presented. Three units of the HIV-1 GP41 trimer are shown in blue, red, and pink, respectively. (F) Tertiary structure of the prefusion RSV glycoprotein F trimer in complex with the antibody motavizumab (PDB accession number 4ZYP). Motavizumab is an experimental monoclonal antibody derived from the FDA-approved drug palivizumab (478). The side views (left) and top views (right) of protein structures are presented. The heavy and light chains of motavizumab are shown in blue and green, respectively. The palivizumab-binding site (amino acid [aa] positions 254 to 277 [479]) is highlighted in red. Three units of the prefusion RSV F trimer are shown in pink, gray, and cyan, respectively.

  • FIG 11
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    FIG 11

    Tertiary structures of HSV-1 thymidine kinase and chemical formulas of acyclic guanosine analogues and acyclic nucleoside phosphonate analogues. (A) The HSV-1 thymidine kinase dimer in complex with acyclovir. Two units of thymidine kinase are shown in pink and orange, respectively. Acyclovir can be phosphorylated by HSV thymidine kinase and cellular enzymes (249). (B to G) Chemical formulas of acyclovir, famciclovir, valacyclovir, ganciclovir, penciclovir, and valganciclovir in the group of acyclic guanosine analogues. (H to K) Chemical formulas of cidofovir, adefovir, tenofovir, and tenofovir alafenamide in the group of acyclic nucleoside phosphonate analogues.

  • FIG 12
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    FIG 12

    Tertiary structures of the HCV NS5A protein and chemical formulas of HCV NS5A inhibitors. (A) Tertiary structure of the HCV NS5A dimer in complex with daclatasvir. Two units of the HCV NS5A dimer are shown in pink and orange, respectively (PDB data were reported in reference 282). (B to F) Chemical formulas of ledipasvir, daclatasvir, ombitasvir, velpatasvir, and elbasvir in the group of HCV NS5A inhibitors. Note that velpatasvir is an experimental inhibitor currently in phase 3 clinical trials.

  • FIG 13
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    FIG 13

    Tertiary structures of HCV NS5B polymerase and chemical formulas of HCV NS5B inhibitors. (A) Tertiary structure of HCV NS5B polymerase in complex with dsDNA, beclabuvir, and sofosbuvir diphosphate (PDB accession numbers 4NLD and 4WTG). Note that beclabuvir and sofosbuvir diphosphate bind to the allosteric site and the catalytic site of the HCV NS5B polymerase, respectively. (B to D) Chemical formulas of beclabuvir, dasabuvir, and sofosbuvir in the group of HCV NS5B inhibitors. Note that beclabuvir is a forthcoming inhibitor in the combination drug of daclatasvir plus asunaprevir plus beclabuvir in phase 4 clinical trials.

  • FIG 14
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    FIG 14

    Tertiary structures of influenza virus proteins (matrix 2, neuraminidase, and RNA polymerase) and chemical formulas of influenza virus inhibitors. (A) Tertiary structure of the influenza A virus matrix 2 protein in complex with amantadine (PDB accession number 2KAD). Movies that simulate the binding of approved antiviral drugs to viral or host proteins are available online (see http://www.virusface.com/). (B) Structure of influenza A virus neuraminidase in complex with zanamivir (PDB accession number 2HTQ). (C) Tertiary structure of influenza virus RNA polymerase in complex with RNA. The RNA polymerases of influenza A virus (left) (PDB accession number 3J9B) and influenza B virus (right) (PDB accession number 4WRT) are illustrated. The PA, PB1, and PB2 subunits of RNA polymerase (see structural details in reference 480) are shown in pink, orange, and gray, respectively. Ribavirin triphosphate targets the catalytic site of the RNA polymerase to inhibit viral replication. Note that the RNA polymerase of influenza A virus is a tetramer (480), but the complete tetramer structure of influenza virus RNA polymerase in complex with its inhibitors is still lacking. (D and E) Chemical formulas of amantadine and rimantadine, which target the matrix 2 protein of influenza virus. (F and G) Chemical formulas of ribavirin and favipiravir, which target the viral RNA polymerase of influenza virus. (H to K) Chemical formulas of zanamivir, laninamivir, peramivir, and oseltamivir, which target the viral neuraminidase of influenza virus.

  • FIG 15
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    FIG 15

    Tertiary structures of interferons and chemical formulas of podofilox, imiquimod, and catechin. (A and B) Cartoon representations of interferon alfa 2a (PDB accession number 4YPG) and interferon alfa 2b (PDB accession number 1RH2). Sequence comparison suggests that amino acid K23 in interferon alfa 2a and amino acid R23 in interferon alfa 2b mark the only sequence difference between interferon alfa 2a and interferon alfa 2b. Structural movies are available online (http://www.virusface.com/). (C to E) Chemical formulas of podofilox, imiquimod, and catechin. Note that catechin is the major ingredient of the botanical drug sinecatechin.

Tables

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  • TABLE 1

    Summary of 9 human infectious diseases treated by approved drugs

    Human virusYr of discovery/isolationAnimal reservoir(s)Transmission routeMean incubation period (range)Mean viral particle diam (nm) (range)Genome type,c length (kb)Protein target(s) of approved drug(s)
    HIV1983Chimpanzee, gorilla, sooty mangabeyBlood borne8–11 yr∼145 (95–166)Linear (+)ssRNA, ∼9.8Protease, RT, integrase, GP41, CCR5
    HCV1989UnclearBlood borne∼7 wk (4–20 wk)∼68 (45–86)Linear (+)ssRNA, ∼9.6NS3/4 protease, NS5A, NS5B polymerase
    Human influenza virus1933Birds, pigs, horsesRespiratory∼2 days (1–4 days)∼120 (84–170)Linear (−)ssRNA, ∼13.6Matrix protein 2, neuraminidase, RNA polymerase
    RSV1957No animal reservoirRespiratory∼5 days (3–8 days)100–1,000Linear (−)ssRNA, ∼15RNA polymerase, glycoproteins
    HBV1963Unclear (bats?)Blood borne90 days (60–150 days)42–46Circular dsDNA, ∼3.3DNA polymerase
    HCMV1956No animal reservoirBlood borne3–12 wk150–200Linear dsDNA, ∼230DNA polymerase
    HSVBefore 1900No animal reservoirSexual or skin contact∼4 days (2–12 days)∼225 (209–239)Linear dsDNA, 152–155DNA polymerase, envelope proteins
    VZV1953No animal reservoirRespiratory10–21 days150–200Linear dsDNA, ∼125DNA polymerase, envelope proteins
    HPV1965No animal reservoira Skin-to-skin contact∼2.9 mo (0.5–8 mo)65–120Circular dsDNA, ∼8—b
    • ↵a Papillomaviruses have been widely found in birds, reptiles, marsupials, and mammals, whereas cross-transfer between species is rare (54).

    • ↵b Instead of targeting HPV proteins directly, three FDA-approved drugs (podofilox, sinecatechins, and imiquimod) act as immunomodulatory or antimitotic agents to treat external genital warts caused by HPV infections.

    • ↵c (+)ssRNA, positive-sense single-stranded RNA; (−)ssRNA, negative-sense single-stranded RNA; dsDNA, double-stranded DNA.

  • TABLE 2

    Summary of 90 approved antiviral drugs in 13 drug groupsf

    Drug groupDrug nameAbbreviationcBrand name(s)dApproved clinical use(s)Mechanism(s) of drug actionApproval datee
    5-substituted 2′-deoxyuridine analoguesIdoxuridineIDUDendridHSV-1Substitutes for thymidine and targets HSV DNA polymerase to inhibit viral DNA synthesisJune 1963
    TrifluridineTFTViropticHSVInhibits HSV DNA replicationApr. 1980
    BrivudineBVDUZostex (Europe)HSV-1, VZVBrivudine triphosphate targets VZV DNA polymerase to inhibit viral DNA synthesis2000
    Nucleoside analoguesVidarabinea VDRVira-AHSV, VZVVidarabine triphosphate competes with dATP to inhibit the activity of viral DNA polymeraseNov. 1976
    EntecavirETVBaracludeHBVInhibits the activity of HBV DNA polymeraseMar. 2005
    TelbivudineLdTTyzekaHBVInhibits the activity of HBV DNA polymeraseOct. 2006
    Pyrophosphate analoguesFoscarnetPFAFoscavirHCMV, HSV (acyclovir resistant)Inhibits the activity of viral DNA polymeraseSept. 1991
    NRTIsZidovudineAZTRetrovirHIVTargets HIV RT and competes with dTTP to inhibit DNA synthesisMar. 1987
    DidanosineddIVidexHIVTargets HIV RT and competes with dATP to inhibit DNA synthesisOct. 1991
    Zalcitabinea ddCHividHIVTargets HIV RT and competes with dCTP to inhibit DNA synthesisJune 1992
    Stavudined4TZeritHIVTargets HIV RT and competes with dTTP to inhibit DNA synthesisJune 1994
    Lamivudine3TCEpivirHIV, HBVTargets viral polymerase and competes with dCTP to inhibit DNA synthesisNov. 1995
    Lamivudine + zidovudine3TC+AZTCombivirHIVTwice-daily, fixed-dose, single-tablet drug used to inhibit the activity of HIV RTSept. 1997
    AbacavirABCZiagenHIVTargets HIV RT and competes with dGTP to inhibit DNA synthesisDec. 1998
    Abacavir + lamivudine + zidovudineABC+3TC+AZTTrizivirHIVTwice-daily, fixed-dose, single-tablet drug of abacavir, lamivudine, and zidovudine used to inhibit the activity of HIV RTNov. 2000
    Emtricitabine(−)FTCEmtrivaHIVTargets HIV RT and competes with dCTP to inhibit DNA synthesisJuly 2003
    NNRTIsNevirapineNVPViramuneHIV-1Binds directly to HIV RT and inhibits DNA synthesisJune 1996
    Delavirdinea DLVRescriptorHIV-1Binds directly to HIV RT and inhibits DNA synthesisApr. 1997
    EfavirenzEFVSustivaHIV-1Binds directly to HIV RT and inhibits DNA synthesisSept. 1998
    EtravirineETRIntelenceHIV-1Binds directly to HIV RT and inhibits DNA synthesisJan. 2008
    RilpivirineRPVEdurantHIV-1Binds directly to HIV RT and inhibits DNA synthesisAug. 2011
    Protease inhibitorsSaquinavirSQVInviraseHIVBlocks the active site of HIV protease to prevent cleavage of viral precursor proteinsDec. 1995
    RitonavirRTVNorvirHIVBlocks the active site of HIV protease to prevent cleavage of viral precursor proteinsMar. 1996
    IndinavirIDVCrixivanHIVBlocks the active site of HIV protease to prevent cleavage of viral precursor proteinsMar. 1996
    NelfinavirNFVViraceptHIVBlocks the active site of HIV protease to prevent cleavage of viral precursor proteinsMar. 1997
    Amprenavira APVAgeneraseHIV-1Blocks the active site of HIV protease to prevent cleavage of viral precursor proteinsApr. 1999
    Lopinavir-ritonavirLPV/rKaletraHIVBlocks the active site of HIV protease to prevent cleavage of viral precursor proteinsSept. 2000
    AtazanavirATVReyatazHIVBlocks the active site of HIV protease to prevent cleavage of viral precursor proteinsJune 2003
    FosamprenavirFPVLexiaHIV-1Blocks the active site of HIV protease to prevent cleavage of viral precursor proteinsOct. 2003
    TipranavirTPVAptivusHIV-1Blocks the active site of HIV protease to prevent cleavage of viral precursor proteinsJune 2005
    DarunavirDRVPrezistaHIVBlocks the active site of HIV protease to prevent cleavage of viral precursor proteinsJune 2006
    Darunavir + cobicistatDRV+COBIPrezcobixHIVHIV protease inhibitors can be combined with cobicistat to inhibit the activity of HIV proteaseJan. 2015
    Atazanavir + cobicistatATV+COBIEvotazHIV Jan. 2015
    Telaprevira TVRIncivekHCV genotype 1HCV protease drugs can inhibit the proteolytic activity of HCV NS3/4A protease; ribavirin and PegIFNα can interfere with HCV replicationMay 2011
    Boceprevira BOCVictrelisHCV genotype 1 May 2011
    SimeprevirSMVOlysioHCV genotype 1 Nov. 2013
    Asunaprevirb ASVSunvepra (Japan)HCV genotype 1 July 2014
    Vaniprevir + ribavirin + PegIFNα-2bVPV+RBV+PegIF-α2bVanihep (Japan)HCV genotype 1 Sept. 2014
    Paritaprevirb PTVViekira PakHCV genotype 1 Dec. 2014
    TechnivieHCV genotype 4 July 2015
    Grazoprevirb GZRZepatierHCV genotype 1 or 4 Jan. 2016
    Integrase inhibitorsRaltegravirRALIsentressHIVTargets HIV integrase to inhibit the integration of viral DNA into human chromosomesOct. 2007
    ElvitegravirEVGVitektaHIVTargets HIV integrase to inhibit the integration of viral DNA into human chromosomesAug. 2012
    DolutegravirDTGTivicayHIVTargets HIV integrase to inhibit the integration of viral DNA into human chromosomesAug. 2013
    Dolutegravir + abacavir + lamivudineDTG+ABC+3TCTriumeqHIVFixed-dose combinations with dolutegravir and NRTIs can target HIV integrase and RT to interrupt viral replicationAug. 2014
    Dolutegravir + lamivudineDTG+3TCDutrebisHIV Feb. 2015
    Entry inhibitorsRSV-IGIVa RSV-IGIVRespiGamRSVRSV-neutralizing antibodies may prevent binding of RSV surface glycoproteins F and GJan. 1996
    PalivizumabPZSynagisRSVMonoclonal antibody that targets the antigenic site of RSV glycoprotein FJune 1998
    DocosanolC22AbrevaHSVMay interfere with binding of viral envelope proteins to cell membrane receptorsJuly 2000
    EnfuvirtideEFVFuzeonHIV-1Blocks HIV GP41 fusion to cell membraneMar. 2003
    MaravirocMVCSelzentryHIVBlocks GP120-CCR5 interaction to inhibit HIV entryAug. 2007
    VZIGa VZIGVZIGVZVIgG antibodies protect patients from VZV infectionFeb. 1981
    VariZIGVariZIGVariZIGVZVIgG antibodies protect patients from VZV infectionDec. 2012
    Acyclic guanosine analoguesAcyclovirACVZoviraxHSV, VZVAcyclovir triphosphate competes with dGTP to inhibit viral DNA polymerase activityMar. 1982
    GanciclovirGCVZirgan, VitrasertHCMVGanciclovir triphosphate targets HCMV DNA polymerase to inhibit viral DNA synthesisJune 1989
    FamciclovirFCVFamvirHSV, VZVFamciclovir triphosphate competes with dGTP to inhibit the activity of viral DNA polymeraseJune 1994
    ValacyclovirVACVValtrexHSV, VZVValacyclovir triphosphate competes with dGTP to inhibit the activity of viral DNA polymeraseJune 1995
    PenciclovirPCVDenavirHSVPenciclovir triphosphate targets HSV DNA polymerase to inhibit viral DNA synthesisSept. 1996
    ValganciclovirVGCVValcyteHCMVValganciclovir triphosphate competes with dGTP to inhibit the activity of viral DNA polymeraseMar. 2001
    Acyclic nucleoside phosphonate analoguesCidofovirCDVVistideHCMV retinitis (AIDS patients)Inhibits the activity of HCMV DNA polymeraseJune 1996
    Tenofovir disoproxil fumarateTDFVireadHIV, HBVCompetes with dATP to inhibit the activity of HIV RT and HBV DNA polymeraseOct. 2001
    Adefovir dipivoxilADVHepseraHBVAdefovir diphosphate competes with dATP to inhibit the activity of HBV DNA polymeraseSept. 2002
    Tenofovir disoproxil fumarate + emtricitabineTDF+(−)FTCTruvadaHIVTruvada is a once-daily fixed-dose single tablet containing 2 drugs to inhibit HIV replicationAug. 2004
    Tenofovir disoproxil fumarate + efavirenz + emtricitabineTDF+EFV+(−)FTCAtriplaHIVAtripla is a once-daily fixed-dose single tablet containing 3 drugs to inhibit HIV replicationJuly 2006
    Tenofovir disoproxil fumarate + rilpivirine + emtricitabineTDF+RPV+(−)FTCComplera, EvipleraHIVComplera is a once-daily fixed-dose single tablet containing 3 drugs to inhibit HIV replicationAug. 2011
    Tenofovir disoproxil fumarate + cobicistat + emtricitabine + elvitegravirTDF+COBI+(−)FTC+EVGStribildHIVStribild is a once-daily fixed-dose single tablet containing 4 drugs to inhibit HIV replicationAug. 2012
    Tenofovir alafenamide + cobicistat + emtricitabine + elvitegravirTAF+COBI+(−)FTC+EVGGenvoyaHIVGenvoya is a once-daily fixed-dose single tablet containing 4 drugs to inhibit HIV replicationNov. 2015
    Tenofovir alafenamide + rilpivirine + emtricitabineTAF+RPV+(−)FTCOdefseyHIVOdefsey is a once-daily fixed-dose single tablet containing 3 drugs to inhibit HIV replicationMar. 2016
    Tenofovir alafenamide + emtricitabineTAF+(−)FTCDescovyHIVDescovy is a once-daily fixed-dose single tablet containing 2 drugs to inhibit HIV replicationApr. 2016
    HCV NS5A and NS5B inhibitorsSofosbuvir + ribavirinSOF+RBVSovaldiHCV genotype 2 or 3Sofosbuvir binds to Mg2+ ions in NS5B polymerase and inhibits HCV replication; ribavirin and PegIFNα can interfere with HCV replicationDec. 2013
    Sofosbuvir + ribavirin + PegIFNαSOF+RBV+PegIFNαSovaldiHCV genotype 1 or 4 Dec. 2013
    Daclatasvir + asunaprevirDCV+ASVDaklinza + Sunvepra (Japan)HCV genotype 1Targets NS5A and NS3/4A protease to prevent HCV replicationJuly 2014
    Ledipasvir + sofosbuvirLDV+SOFHarvoniHCV genotype 1Harvoni inhibits HCV NS5A and NS5B polymerase to prevent RNA replicationOct. 2014
    Sofosbuvir+ simeprevirSOF+SMVSovaldi + OlysioHCV genotype 1Sofosbuvir and simeprevir target HCV NS5B and NS3/4 protease, respectivelyNov. 2014
    Ombitasvir + dasabuvir + paritaprevir + ritonavirOBV+DAS+PTV+RTVViekira PakHCV genotype 1Viekira Pak is a multiclass combination drug approved for treatment of HCV genotype 1 infection; inhibits activities of HCV NS5A, NS5B polymerase, and NS3/4A proteaseDec. 2014
    Ombitasvir + paritaprevir + ritonavirOBV+PTV+RTVTechnivieHCV genotype 4Technivie is used with ribavirin to treat HCV genotype 4 infection; inhibits HCV NS5A and NS3/4A proteaseJuly 2015
    Daclatasvir + sofosbuvirDCV+SOFDaklinza + SovaldiHCV genotype 3Inhibits activities of HCV NS5A and NS5B polymeraseJuly 2015
    Elbasvir + grazoprevirEBR+GZRZepatierHCV genotype 1 or 4Elbasvir and grazoprevir inhibit activities of NS5A and NS3/4A protease, respectivelyJan. 2016
    Influenza virus inhibitorsAmantadinea AMTSymmetrelInfluenza virus ATargets viral matrix protein 2 to inhibit viral uncoatingOct. 1966
    RibavirinRBVCopegus, Rebetol, VirazoleHCV, RSV, hemorrhagic feverRibavirin triphosphate targets viral RNA polymerase to inhibit mRNA synthesisDec. 1985
    RimantadineRIMFlumadineInfluenza virus ATargets matrix protein 2 to inhibit viral uncoatingSept. 1993
    ZanamivirZANRelenzaInfluenza viruses A and BTargets viral neuraminidase to inhibit virus release from host cellsJuly 1999
    OseltamivirOTVTamifluInfluenza viruses A and BTargets viral neuraminidase to inhibit virus release from host cellsOct. 1999
    Laninamivir octanoateLOInavir (Japan)Influenza viruses A and BTargets viral neuraminidase to inhibit virus release from host cellsSept. 2010
    PeramivirPRVRapivabInfluenza viruses A and BTargets viral neuraminidase to inhibit virus release from host cellsDec. 2014
    FavipiravirFPVAvigan (Japan)Influenza viruses A, B, and CFavipiravir-ribofuranosyl-5′-triphosphate inhibits the activity of influenza RNA polymeraseMar. 2014
    Interferons, immunostimulators, oligonucleotides, and antimitotic inhibitorsPegylated interferon alfa 2bPegIFNα-2bIntron-A, PegIntronHBV, HCVPegIFNα-2b is used to treat patients with HBV and/or HCV infectionJune 1986
    Interferon alfacon 1a CIFNInfergenHCV genotype 1Interferon alfacon 1 can be used with ribavirin to treat HCV infectionOct. 1997
    Pegylated interferon alfa 2b + ribavirinPegIFNα-2b+RBVRebetronHCVPegIFNα-2b is used with ribavirin to treat patients with HCV infectionJune 1998
    Pegylated interferon alfa 2aPegIFN-α2aPegasys, Roferon-AHBV, HCVUsed with or without ribavirin to treat patients with HCV and/or HBV infectionOct. 2002
    Fomivirsena FMVVitraveneHCMVAntisense RNA interrupts HCMV gene expressionAug. 1998
    PodofiloxPDXCondyloxHPV-related diseasesAntimitotic drug that interrupts cell divisionDec. 1990
    ImiquimodIQMAldaraHPV-related diseasesStimulates cytokines to clear external genital wartsFeb. 1997
    SinecatechinsSINEVeregenHPV-related diseasesBotanical drug that acts as an immunomodulator to interfere with HSV-induced pathwaysOct. 2006
    • ↵a Discontinued antiviral drug (amantadine, amprenavir, boceprevir, delavirdine, fomivirsen, RSV-IGIV, VZIG, telaprevir, vidarabine, zalcitabine, and interferon alfacon 1).

    • ↵b Different combination drugs. The combination of asunaprevir plus daclatasvir was approved to treat HCV genotype 1 infection in Japan, the combination of grazoprevir plus elbasvir was approved to treat HCV genotype 1 or 4 infection, the combination of paritaprevir plus ombitasvir plus dasabuvir plus ritonavir was approved to treat HCV genotype 1 infection, and the combination of paritaprevir plus ombitasvir plus ritonavir was approved to treat HCV genotype 4 infection.

    • ↵c Abbreviations commonly used in literature. The first four letters are used if drug abbreviations could not be found (e.g., sinecatechins are abbreviated SINE).

    • ↵d Antiviral drugs that have been approved in either Japan or Europe but not in the United States are indicated by “(Japan)” or “(Europe).”

    • ↵e Only the earliest time is listed if several approval dates for different clinical applications were found.

    • ↵f Table S1 in the supplemental material summarizes information on drug databases and chemical formulas. Information on dosage and administration of approved antiviral drugs is available online (see http://www.fda.gov/ and http://www.virusface.com/).

  • TABLE 3

    Summary of forthcoming antiviral treatments in phase 3 trials

    Antiviral drugViral infection% efficacyaMechanism(s) of actionStudy progressb
    Sofosbuvir + velpatasvirHCV genotypes 1–697.4Inhibit activities of HCV NS5B polymerase and NS5A, respectivelyPhase 3, completed
    Daclatasvir + asunaprevirHCV genotype 186.4Daclatasvir, asunaprevir, and beclabuvir inhibit activities of NS5A, NS3/4A protease, and NS5B, respectivelyPhase 4, ongoing
    Daclatasvir + asunaprevir + beclabuvirHCV genotype 191.5 Phase 3, ongoing
    FV100VZV87.6Inhibits activity of the VZV DNA polymerasec Phase 3, ongoing
    LetermovirHCMV71Targets the pUL56 subunit of the HCMV terminase complex to block viral DNA processing and/or packagingd Phase 3, ongoing
    • ↵a For HCV inhibitors, drug efficacy is measured by the SVR12 (see the text). For the VZV inhibitor FV100, drug efficacy is measured by the incidence of patients without postherpetic neuralgia after treatment at 90 days. For the HCMV inhibitor letermovir, drug efficacy is measured by the incidence of successful prophylaxis after treatment at 12 weeks (392).

    • ↵b Clinical data were extracted from ClinicalTrials.gov (see https://www.clinicaltrials.gov/) in April 2016.

    • ↵c See reference 385.

    • ↵d See references 389 and 390.

  • TABLE 4

    Control of viral infections using approved vaccines and/or antiviral drugs

    GroupFamilyVirus(es)VaccineAntiviral drug
    I (dsDNA) Adenoviridae Human adenovirusYesOff-label druga
    Hepadnaviridae HBVYesYes
    Herpesviridae VZV (shingles)YesYes
    HSV, HCMVNoYes
    EBVNoNo
    Human herpesvirus 6NoOff-label druga
    Papillomaviridae HPVYesYesb
    Polyomaviridae Human polyomavirusNoOff-label druga
    Poxviridae Variola virus (smallpox)YesOff-label druga
    II (ssDNA) Parvoviridae Human parvovirusNoNo
    III (dsRNA) Reoviridae RotavirusYesNo
    IV [(+)ssRNA] Astroviridae Human astrovirusNoNo
    Caliciviridae Human sapovirusNoNo
    Coronaviridae Human coronavirusNoNo
    Flaviviridae HCVNoYes
    Yellow fever virusYesNo
    Japanese encephalitis virusYesNo
    Dengue, West Nile, Zika virusesNoNo
    Hepeviridae Hepatitis E virusYesc No
    Picornaviridae Hepatitis A virus, poliovirusYesNo
    Norovirus, rhinovirusNoNo
    Togaviridae Rubella virusYesNo
    Chikungunya virusNoNo
    V [(−)ssRNA] Arenaviridae Lassa, Junin, Machupo virusesNoNo
    Filoviridae Ebola, Marburg virusesNoNo
    Orthomyxoviridae Influenza virusYesYes
    Paramyxoviridae RSVNoYes
    Measles, mumpsYesNo
    Hendra, Nipah virusesNoOff-label druga
    Rhabdoviridae RabiesYesNo
    VI [(+)ssRNA] Retroviridae HIVNoYes
    • ↵a Cidofovir might be an off-label prescription to treat human polyomavirus, adenovirus, and smallpox. Foscarnet, ganciclovir, and cidofovir might be off-label drugs for HHV-6. Ribavirin might be an off-label prescription for Hendra and Nipah virus infections.

    • ↵b Three FDA-approved drugs (sinecatechins, podofilox, and imiquimod) are available for the treatment of external genital warts caused by HPV (354). However, these drugs may not target HPV proteins directly.

    • ↵c The HEV vaccine HEV239 was approved in China in 2012.

Additional Files

  • Figures
  • Tables
  • Supplemental material

    • Supplemental file 1 -

      Table S1 (Summary of approved drugs against 9 human infectious diseases, including information from drug formulas and drug records in public databases.)

      PDF, 323K

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Approved Antiviral Drugs over the Past 50 Years
Erik De Clercq, Guangdi Li
Clinical Microbiology Reviews Jun 2016, 29 (3) 695-747; DOI: 10.1128/CMR.00102-15

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Approved Antiviral Drugs over the Past 50 Years
Erik De Clercq, Guangdi Li
Clinical Microbiology Reviews Jun 2016, 29 (3) 695-747; DOI: 10.1128/CMR.00102-15
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  • Top
  • Article
    • SUMMARY
    • INTRODUCTION
    • OVERVIEW OF NINE HUMAN VIRUSES
    • 5-SUBSTITUTED 2′-DEOXYURIDINE ANALOGUES
    • NUCLEOSIDE ANALOGUES
    • PYROPHOSPHATE ANALOGUES
    • NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
    • NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
    • PROTEASE INHIBITORS
    • INTEGRASE INHIBITORS
    • ENTRY INHIBITORS
    • ACYCLIC GUANOSINE ANALOGUES
    • ACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGUES
    • HCV NS5A/NS5B INHIBITORS
    • INFLUENZA VIRUS INHIBITORS
    • INTERFERONS, IMMUNOSTIMULATORS, OLIGONUCLEOTIDES, AND ANTIMITOTIC INHIBITORS
    • FORTHCOMING ANTIVIRAL INHIBITORS
    • ANTIVIRAL STRATEGIES AGAINST CURRENT AND EMERGING INFECTIOUS DISEASES
    • CONCLUSIONS AND FUTURE PERSPECTIVES
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
    • Author Bios
  • Figures & Data
  • Info & Metrics
  • PDF

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