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In this era spanning more than 60 years (from the early 1960s till today (2023), a broad variety of actors played a decisive role: Piet De Somer, Tom C. Merigan, Paul A. Janssen, Maurice Hilleman, and Georges Smets. Two protagonists (Antonín Holý and John C. Martin) formed with me a unique triangle (the Holý Trinity). Walter Fiers' group (with the help of Jean Content) contributed to the cloning of human β-interferon, and Piet Herdewijn accomplished the chemical synthesis of an array of anti-HIV 2',3'-dideoxynucleoside analogues. Rudi Pauwels, Masanori Baba, Dominique Schols, Johan Neyts, Lieve Naesens, Anita Van Lierde, Graciela Andrei, Robert Snoeck and Dirk Daelemans, as members of my team, helped me in achieving the intended goal, the development of a selective therapy for virus infections. The collaboration with "Lowie" (Guangdi Li) generated a new dimension for the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Many acyclic nucleoside phosphonates such as cidofovir, adefovir dipivoxil, tenofovir disoproxil fumarate, and tenofovir alafenamide have been marketed for the treatment or prophylaxis of infectious diseases. Here, this review highlights potent acyclic nucleoside phosphonates for their potential in the treatment of retrovirus (e.g., human immunodeficiency virus) and DNA virus (e.g., adeno-, papilloma-, herpes- and poxvirus) infections. If properly assessed and/or optimized, some potent acyclic nucleoside phosphonates can be possibly applied in the control of current and emerging infectious diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir., (© 2021 Wiley Periodicals LLC.)

Remdesivir (GS-5734, Veklury®) has remained the only antiviral drug formally approved by the US FDA for the treatment of Covid-19 (SARS-CoV-2 infection). Its key structural features are the fact that it is a C-nucleoside (adenosine) analogue, contains a 1'-cyano function, and could be considered as a ProTide based on the presence of a phosphoramidate group. Its antiviral spectrum and activity in animal models have been well established and so has been its molecular mode of action as a delayed chain terminator of the viral RdRp (RNA-dependent RNA polymerase). Its clinical efficacy has been evaluated, but needs to be optimized with regard to timing, dosage and duration of treatment, and route of administration. Safety, toxicity and pharmacokinetics need to be further addressed, and so are its potential combinations with other drugs such as corticosteroids (i.e. dexamethasone) and ribavirin., (Copyright © 2021 Elsevier Inc. All rights reserved.)

During the last forty years we have witnessed impressive advances in the field of antiviral drug discovery culminating with the introduction of therapies able to stop human immunodeficiency virus (HIV) replication, or cure hepatitis C virus infections in people suffering from liver disease. However, there are important viral diseases without effective treatments, and the emergence of drug resistance threatens the efficacy of successful therapies used today. In this review, we discuss strategies to discover antiviral compounds specifically designed to combat drug resistance. Currently, efforts in this field are focused on targeted proteins (e.g. multi-target drug design strategies), but also on drug conformation (either improving drug positioning in the binding pocket or introducing conformational constraints), in the introduction or exploitation of new binding sites, or in strengthening interaction forces through the introduction of multiple hydrogen bonds, covalent binding, halogen bonds, additional van der Waals forces or multivalent binding. Among the new developments, proteolysis targeting chimeras (PROTACs) have emerged as a valid approach taking advantage of intracellular mechanisms involving protein degradation by the ubiquitin-proteasome system. Finally, several molecules targeting host factors (e.g. human dihydroorotate dehydrogenase and DEAD-box polypeptide 3) have been identified as broad-spectrum antiviral compounds. Implementation of herein described medicinal chemistry strategies are expected to contribute to the discovery of new drugs effective against current and future threats due to emerging and re-emerging viral pandemics.

On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b - the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide., Competing Interests: The authors declare no conflicts of interest in this work., (© 2020 Miao et al.)

Background: As an important anti-HBV drug, pegylated interferon α (PegIFNα) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses., Methods: We analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFNα-2a or PegIFNα-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72., Results: HBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value < 0.05). HBV RNA ≤ 1000 copies/mL was an optimized cutoff at week 12 that offered better prediction than other HBV biomarkers. This optimized cutoff plus patient age, HBV genotype B, and HBeAg offered a strong estimation of HBeAg seroconversion (accuracy 95.2%, true negative rate 99.8%)., Conclusion: HBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.

Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3-deazaneplanocin A, galidesivir, GS-6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS-6620, remdesivir and pyrazofurin) are C-nucleosides, and two of them (GS-6620, remdesivir) also contain a phosphoramidate part. The C-nucleoside and phosphoramidate (and for the adenine analogues the 1'-cyano group as well) may be considered as essential attributes for their antiviral activity., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fifty years of research (1968-2018) toward the identification of selective antiviral drugs have been primarily focused on antiviral compounds active against DNA viruses (HSV, VZV, CMV, HBV) and retroviruses (HIV). For the treatment of HSV infections the aminoacyl esters of acyclovir were designed, and valacyclovir became the successor of acyclovir in the treatment of HSV and VZV infections. BVDU (brivudin) still stands out as the most potent among the marketed compounds for the treatment of VZV infections (i.e., herpes zoster). In the treatment of HIV infections 10 tenofovir-based drug combinations have been marketed, and tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) have also proved effective in the treatment of HBV infections. As a spin-off of our anti-HIV research, a CXCR4 antagonist AMD-3100 was found to be therapeutically useful as a stem cell mobilizer, and has since 10 years been approved for the treatment of some hematological malignancies.

Tenofovir (TFV) is the cornerstone of the treatment and prophylaxis of HIV infections. It has been routinely used in its prodrug form TDF (tenofovir disoproxil fumarate) combined with emtricitabine ((-)FTC) and other antiretroviral agents. TDF has now been replaced by TAF (tenofovir alafenamide) which allows better uptake by the lymphoid tissue. In combination with elvitegravir (E), cobicistat (C), emtricitabine (F), TAF can be advocated as an STR (single tablet regimen, Genvoya®) for the treatment of HIV infections. In this combination, E and C may in the future be replaced by bictegravir. The prophylaxis of HIV infection is momentarily based upon Truvada®, the combination of F with TDF, which in the future may also be replaced by TAF. TAF (Vemlidy®) has also replaced TDF (Viread®) for the treatment of hepatitis B virus (HBV) infections. Both TDF and TAF offer little or no risk for virus-drug resistance. As compared to TDF, TAF limits the risk for nephrotoxicity and loss of bone mineral density. What remains to be settled, however, before the universal use of TAF could be recommended, is its safety during pregnancy and its applicability in the treatment of tuberculosis, in combination with rifampicin., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.

One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients., (Copyright © 2017. Published by Elsevier B.V.)

There are currently no approved antiviral therapies against medically important human flaviviruses. The imino-C-nucleoside BCX4430 shows broad-spectrum antiviral activity against a wide range of RNA viruses. Here, we demonstrate that BCX4430 inhibits tick-borne species of the genus Flavivirus; however, the antiviral effect varies against individual species. Micro-molar BCX4430 levels inhibited tick-borne encephalitis virus (TBEV); while, approximately 3-8-fold higher concentrations were needed to inhibit louping ill virus and Kyasanur Forest disease virus. Moreover, the compound strongly inhibited in vitro replication of West Nile virus, a typical mosquito-transmitted flavivirus. Two chemical forms of the compound, i.e. BCX4430 and BCX4430 hydrochloride, were compared and both exerted similar inhibitory profiles in our in vitro antiviral assay systems and no or negligible cytotoxicity in porcine kidney stable and Vero cells. The obtained data indicate that, in addition to mosquito-borne flaviviruses, the compound has strong antiviral activity against members of the TBEV serocomplex., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Tenofovir alafenamide (TAF) can be considered a new prodrug of tenofovir (TFV), as successor of tenofovir disoproxil fumarate (TDF). It is in vivo as potent against human immunodeficiency virus (HIV) at a 30-fold lower dose (10mg) than TDF (300mg). TAF has been approved in November 2015 (in the US and EU), as a single-tablet regimen (STR) containing 150mg elvitegravir (E), 150mg cobicistat (C), 200mg emtricitabine [(-)FTC] (F) and 10mg TAF, marketed as Genvoya®, on 01 March 2016 in the US as an STR containing 25mg rilpivirine (R), 200mg F and 25mg TAF, marketed as Odefsey®, and on 4 April 2016 in the US, as an STR containing 200mg F and 25mg TAF, marketed as Descovy®, for the treatment of HIV infections. STR combinations containing TAF and emtricitabine could be paired with a range of third agents, for example, darunavir and cobicistat. TAF has a much lower risk of kidney toxicity or bone density changes than TDF, and also offers long-term potential in the pre-exposure prophylaxis (PrEP) of HIV infections. TAF is specifically accumulated in lymphatic tissue, and in the liver, and hence also holds great potential for the treatment of hepatitis B virus (HBV) infections. Akin to TDF, TAF is converted intracellularly to TFV. Its active diphosphate metabolite (TFVpp) is targeted at the RNA-dependent DNA polymerase (reverse transcriptase) of either HIV or HBV., (Copyright © 2016 Elsevier Inc. All rights reserved.)

There is growing evidence that Zika virus (ZIKV) can cause devastating infant brain defects and other neurological disorders in humans. However, no specific antiviral therapy is available at present. We tested a series of 2'-C- or 2'-O-methyl-substituted nucleosides, 2'-C-fluoro-2'-C-methyl-substituted nucleosides, 3'-O-methyl-substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C-azido substitution, heterobase-modified nucleosides, and neplanocins for their ability to inhibit ZIKV replication in cell culture. Antiviral activity was identified when 2'-C-methylated nucleosides were tested, suggesting that these compounds might represent promising lead candidates for further development of specific antivirals against ZIKV., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Tick-borne encephalitis (TBE) represents one of the most serious arboviral neuro-infections in Europe and northern Asia. As no specific antiviral therapy is available at present, there is an urgent need for efficient drugs to treat patients with TBE virus (TBEV) infection. Using two standardised in vitro assay systems, we evaluated a series of 29 nucleoside derivatives for their ability to inhibit TBEV replication in cell lines of neuronal as well as extraneural origin. The series of tested compounds included 2'-C- or 2'-O-methyl substituted nucleosides, 2'-C-fluoro-2'-C-methyl substituted nucleosides, 3'-O-methyl substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C-azido substitution, heterobase modified nucleosides and neplanocins. Our data demonstrate a relatively stringent structure-activity relationship for modifications at the 2', 3', and 4' nucleoside positions. Whereas nucleoside derivatives with the methylation at the C2' position or azido modification at the C4'position exerted a strong TBEV inhibition activity (EC50 from 0.3 to 11.1 μM) and low cytotoxicity in vitro, substitutions of the O2' and O3' positions led to a complete loss of anti-TBEV activity (EC50 > 50 μM). Moreover, some structural modifications of the heterobase moiety resulted in a high increase of cytotoxicity in vitro. High antiviral activity and low cytotoxicity of C2' methylated or C4' azido substituted pharmacophores suggest that such compounds might represent promising candidates for further development of potential therapeutic agents in treating TBEV infection., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2'-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2'-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

In this paper, a series of imidazo[2,l-b][1,3,4]thiadiazoles have been prepared by reacting 2-amino-1,3,4-thiadiazole with various phenacyl bromides in alcohol. The structures of all the derivatives were con- firmed by IR, NMR and mass spectroscopy. All the derivatives have been tested for cytostatic activity against human T-lymphocyte cells (CEM), human cervix carcinoma cells (HeLa), murine leukemia cell line (L1210), and antiviral activity. Among the tested compounds, derivatives 5b, 5c, and 7a were cytostatic between 49-63 mM against Hela and 7g was cytotoxic at 23 mM against L1210 and CEM cell lines. Compounds 5h and 7h emerged as antiviral agents with slight activity against influenza A and B.

Two new C-nucleoside analogues, BCX4430, an imino-C-nucleoside, and GS-6620, a phosphoramidate derivative of 1'-cyano-2'-C-methyl-4-aza-7,9-dideazaadenosine 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.

Chronic hepatitis B virus (HBV) infection remains an important global burden with an estimated 240 million HBV carriers worldwide and more than half a million people dying annually from the consequences of the HBV infection. Besides interferon and pegylated interferon, there are five antiviral drugs [lamivudine, adefovir (dipivoxil), entecavir, telbivudine, and tenofovir disoproxil fumarate] that have proved effective in the treatment of chronic hepatitis B. These five antiviral drugs interfere with viral DNA synthesis, which consists of a step reminiscent of the reverse transcriptase step in the replicative cycle of HIV. None of the antiviral drugs, or interferon, are capable of eradicating the covalently closed circular DNA, which remains settled as an episome within the virus-infected hepatocytes. In the short-term (1-3 years), the use of antiviral treatment is aimed at reducing viral DNA below levels of detection, whereas in the long term (10 years and, possibly, lifelong), treatment is aimed at reducing the progression to cirrhosis, hepatocellular carcinoma, liver decompensation, and death. As long as the virus can hide as the episomal covalently closed circular DNA, attempts to envisage a definite cure of the HBV infection may seem fortuitous., (Copyright © 2015 John Wiley & Sons, Ltd.)

We have developed a series of N(2) -(1-(substituted-aryl)piperidin-4-yl)-N(6) -mesityl-9H-purine-2,6-diamine derivatives as potent antiviral agents. Preliminary biological evaluation indicated that nearly half of them possessed remarkable HIV inhibitory potencies in cellular assays. In particular, FZJ13 appeared to be the most notable one, which displayed anti-HIV-1 activity compared to 3TC. Moreover, an unexpected finding was that FZJ05 displayed significant potency against influenza A/H1N1 (strain A/PR/8/34) in Madin-Darby canine kidney cells with EC50 values much lower than those of ribavirin, amantadine, and rimantadine. The results suggest that these novel purine derivatives have the potential to be further developed as new therapeutic agents against HIV-1 or influenza virus., (© 2015 John Wiley & Sons A/S.)

Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), 2'-C-methyladenosine (2'-CMA), and 2'-C-methylcytidine (2'-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 ± 0.4 μM for 7-deaza-2'-CMA, 7.1 ± 1.2 μM for 2'-CMA, and 14.2 ± 1.9 μM for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ∼50 μM). The anti-TBEV effect of 2'-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2'-CMA showed no detectable cellular toxicity (CC50 > 50 μM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2'-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2'-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Anno 2015, the race for developing the ideal therapy, or what is now called "cure," for hepatitis C virus infection has continued unabatedly. The targets (NS3/4A protease, NS5A protein, and NS5B polymerase) have remained the same, and the number of compounds [direct-acting antivirals (DAAs)] interacting with these targets has continued to increase. Whereas pan-genotypic activity has remained a mandatory requirement, the problem of virus drug resistance has become less crucial. The need for combining DAAs acting at different sites has remained compelling, with the drugs used for combinations emanating from the same pharmaceutical company, that is, Gilead (sofosbuvir and ledipasvir) (Gilead Sciences, Foster City, CA, USA) (AbbVie, North Chicago, IL, USA), AbbVie (ABT/r, ombitasvir, and dasabuvir), and BMS (Bristol-Myers Squibb), (New York City, NY, USA) (asunaprevir and daclatasvir) among the leading contenders. At stake is the definitive cure of HCV infection [as reflected by a sustained viral response (SVR) after 12 weeks of treatment]. This SVR is expected to reduce cirrhosis and hepatocellular carcinoma, two complications inherently linked to HCV infection. Unlike hepatitis B virus and human immunodeficiency virus, HCV infection can be definitely and permanently cured by antiviral therapy because HCV has no long-term reservoir in the body. Peginterferon combined with ribavirin and even the first-wave protease inhibitors telaprevir and boceprevir now belong to the milestones that had an important, although historical, role in the final conquest of hepatitis C., (Copyright © 2015 John Wiley & Sons, Ltd.)

Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2'-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses., (© 2015 Wiley Periodicals, Inc.)

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for children under 5 years of age and causes excess mortality in the elderly. There is still no approved vaccine available, although the disease can be curtailed by RSV-specific monoclonal antibody. The only antiviral drug approved for the treatment of RSV infection is ribavirin aerosol, but this treatment is cumbersome and its efficacy is questionable. A new antiviral, GS-5806, which interferes with virus-cell fusion, has proven efficacious in experimental RSV infections in adults., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

In the current context of antiviral drug development, which has been traditionally dominated by herpesviruses, human immunodeficiency virus (HIV) and hepatitis C virus (HCV), a new viral target has been recently gained unforeseen attention, Ebola virus. Ten nucleoside analogues, or categories thereof, are reviewed for their therapeutic potential as antiviral drugs: (i) BCX4430, a C-nucleoside; (ii) 4'-azido-, 4'-cyano-, and 4'-ethynyl derivatives; (iii) 4'-thionucleosides; (iv) cordycepin (3'-deoxyadeosine); (v) pyrazofurin, another C-nucleoside; (vi) neplanocin A analogues; (vii) EICAR, a ribavirin analogue; (viii) GR-92938X, a double carboxamide; (ix) sofosbuvir (Solvaldi(®)), a 2'-C-methylnucleoside; and (x) favipiravir (T-705), a pyrazine analogue.

Within less than a year after its epidemic started (in December 2013) in Guinea, Ebola virus (EBOV), a member of the filoviridae, has spread over a number of West-African countries (Guinea, Sierra Leone and Liberia) and gained allures that have been unprecedented except by human immunodeficiency virus (HIV). Although EBOV is highly contagious and transmitted by direct contact with body fluids, it could be counteracted by the adequate chemoprophylactic and -therapeutic interventions: vaccines, antibodies, siRNAs (small interfering RNAs), interferons and chemical substances, i.e. neplanocin A derivatives (i.e. 3-deazaneplanocin A), BCX4430, favipiravir (T-705), endoplasmic reticulum (ER) α-glucosidase inhibitors and a variety of compounds that have been found to inhibit EBOV infection blocking viral entry or by a mode of action that still has to be resolved. Much has to be learned from the mechanism of action of the compounds active against VSV (vesicular stomatitis virus), a virus belonging to the rhabdoviridae, that in its mode of replication could be exemplary for the replication of filoviridae., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The direct-acting antivirals (DAAs) currently in development for treatment of hepatitis C fall into four categories: (i) NS3/4A protease inhibitors: ABT-450/r, faldaprevir, asunaprevir, GS-9256, vedroprevir (GS-9451), danoprevir, MK-5172, vaniprevir, sovaprevir, ACH-2684, narlaprevir and simeprevir, in addition to those that are already developed [telaprevir (Incivek®) and boceprevir (Victrelis®)], (ii) NS5A protein inhibitors: ABT-267, daclatasvir, ledipasvir, ACH-2928, ACH-3102, PPI-668, AZD-7295, MK-8742, and GSK 2336805; (iii) NS5B (nucleoside-type) polymerase inhibitors: sofosbuvir (now approved by the FDA since 6 December 2013), GS-0938, mericitabine, VX-135, ALS 2158 and TMC 649128; (iv) NS5B (non-nucleoside-type) polymerase inhibitors: VX-222, ABT-072, ABT-333, deleobuvir, tegobuvir, setrobuvir, VCH-916, VCH-759, BMS-791325 and TMC-647055. Future drug combinations will likely exist of two or more DAAs belonging to any of the 4 categories, with the aim to achieve (i) pan-genotypic hepatitis C virus (HCV) activity, (ii) little or no risk for resistance; (iii) short duration (i.e. 12 weeks) of treatment, and (iv) a sustained viral response (SVR) and definite cure of the disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Three libraries of adamantane derivatives were synthesized and evaluated for antiviral and antiproliferative activities against a broad variety of DNA and RNA viruses. Whereas none of the compounds exhibit antiviral activity at subtoxic concentrations, antiproliferative activity was found against murine leukemia cells (L1210), human T-lymphocyte cells (CEM), and cervix carcinoma cells (HeLa) for 4, 8, and 10., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this second part of "Dancing with antivirals as chemical formulae" I will focus on a number of chemical compounds that in the last few years have elicited more than common attraction from a commercial viewpoint: (i) favipiravir (T-705), as it is active against influenza, but also several other RNA viruses; (ii) neuraminidase inhibitors such as zanamivir and oseltamivir; (iii) peramivir and laninamivir octanoate, which might be effective against influenza virus following a single (intravenous or inhalation) administration; (iv) sofosbuvir, the (anticipated) cornerstone for the interferon-free therapy of HCV infections; (v) combinations of DAAs (direct antiviral agents) to achieve, in no time, a sustained virus response (SVR) against HCV infection; (vi) HIV protease inhibitors, the latest and most promising being darunavir; (vii) the integrase inhibitors (INIs) (raltegravir, elvitegravir, dolutegravir), representing a new dimension in the anti-HIV armamentarium; (viii), a new class of helicase primase inhibitors (HPIs) that may exceed acyclovir and the other anti-herpes compounds in both potency and safety; (ix) CMX-001, as the latest of Dr. Antonín Holý's legacy for its activity against poxviruses and CMV infections, and (x) noroviruses for which the ideal antiviral compounds are still awaited for., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Prominent in the current stage of antiviral drug development are: (i) for human immunodeficiency virus (HIV), the use of fixed-dose combinations (FDCs), the most recent example being Stribild(TM); (ii) for hepatitis C virus (HCV), the pleiade of direct-acting antivirals (DAAs) that should be formulated in the most appropriate combinations so as to obtain a cure of the infection; (iii)-(v) new strategies (i.e., AIC316, AIC246, and FV-100) for the treatment of herpesvirus infections: herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), respectively; (vi) the role of a new tenofovir prodrug, tenofovir alafenamide (TAF) (GS-7340) for the treatment of HIV infections; (vii) the potential use of poxvirus inhibitors (CMX001 and ST-246); (viii) the usefulness of new influenza virus inhibitors (peramivir and laninamivir octanoate); (ix) the position of the hepatitis B virus (HBV) inhibitors [lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF)]; and (x) the potential of new compounds such as FGI-103, FGI-104, FGI-106, dUY11, and LJ-001 for the treatment of filoviruses (i.e., Ebola). Whereas for HIV and HCV therapy is aimed at multiple-drug combinations, for all other viruses, HSV, CMV, VZV, pox, influenza, HBV, and filoviruses, current strategies are based on the use of single compounds., (© 2013 Wiley Periodicals, Inc.)

This review highlights ten "hot topics" in current antiviral research: (i) new nucleoside derivatives (i.e., PSI-352938) showing high potential as a direct antiviral against hepatitis C virus (HCV); (ii) cyclopropavir, which should be further pursued for treatment of human cytomegalovirus (HCMV) infections; (iii) North-methanocarbathymidine (N-MCT), with a N-locked conformation, showing promising activity against both α- and γ-herpesviruses; (iv) CMX001, an orally bioavailable prodrug of cidofovir with broad-spectrum activity against DNA viruses, including polyoma, adeno, herpes, and pox; (v) favipiravir, which is primarily pursued for the treatment of influenza virus infections, but also inhibits the replication of other RNA viruses, particularly (-)RNA viruses such as arena, bunya, and hanta; (vi) newly emerging antiarenaviral compounds which should be more effective (and less toxic) than the ubiquitously used ribavirin; (vii) antipicornavirus agents in clinical development (pleconaril, BTA-798, and V-073); (viii) natural products receiving increased attention as potential antiviral drugs; (ix) antivirals such as U0126 targeted at specific cellular kinase pathways [i.e., mitogen extracellular kinase (MEK)], showing activity against influenza and other viruses; and (x) two structurally unrelated compounds (i.e., LJ-001 and dUY11) with broad-spectrum activity against virtually all enveloped RNA and DNA viruses., (© 2012 Wiley Periodicals, Inc.)

A chemical structure is a joy forever, and this is how I perceived the chemical structures of a number of antiviral compounds with which I have been personally acquainted over the past 3 decades: (1) amino acid esters of acyclovir (i.e. valaciclovir); (2) 5-substituted 2'-deoxyuridines (i.e. brivudin); (3) 2',3'-dideoxynucleoside analogues (i.e. stavudine); (4) acyclic nucleoside phosphonates (ANPs) (i.e. cidofovir, adefovir); (5) tenofovir disoproxil fumarate (TDF) and drug combinations therewith; (6) tenofovir alafenamide (TAF, GS-7340), a new phosphonoamidate prodrug of tenofovir; (7) pro-prodrugs of PMEG (i.e. GS-9191 and GS-9219); (8) new ANPs: O-DAPy and 5-aza-C phosphonates; (9) non-nucleoside reverse transcriptase inhibitors (NNRTIs): HEPT and TIBO derivatives; and (10) bicyclam derivatives (i.e. AMD3100)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

At the 25th International Conference on Antiviral Research, I received a special recognition for my contribution to the International Society of Antiviral Research over a period of 25 years (from 1987 until 2012). This review follows the theme of my presentation at that event, which comprised 10 reminiscences, all with a Japanese connection concerning the success, or otherwise, in the clinical development of: double- and single-stranded polynucleotides; suramin, a polysulfonate; dextran sulfate, a polysulfate; brivudin; BVaraU; 2',3'-dideoxynucleoside analogues; HEPT; adefovir and tenofovir; CXCR4 antagonists; and elvitegravir.

A new compound library that contained 20 hinged benzimidazole-coumarin hybrids and their β-d-ribofuranosides was established. The anti-hepatitis C virus (HCV) activity of all novel coumarin derivatives, which were obtained by use of organic synthetic methods, was tested. Two of these hybrids exhibited appealing EC50 values of as low as 3.0 and 5.5 μM. The best selectivity index was 14. The incorporation of a d-ribofuranose into the hinged hybrids provided the corresponding nucleosides with the β configuration, one of which inhibited HCV replication with an EC50 value of 20 μM. Additionally, the structure-activity relationship is elucidated on the basis of the functional groups that were attached to the nuclei of benzimidazole, coumarin, and ribofuranose of the hybrids., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Vaccination is possible to prevent infections with some viruses: hepatitis B virus (HBV), varicella-zoster virus (VZV), influenza A and B viruses, Yellow fever virus and poliovirus; but not for others: human immunodeficiency virus (HIV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), and most hemorrhagic fever viruses (HFV) (except for Yellow fever virus). Antiviral therapy is obviously needed to control those infections that are not amenable to prophylaxis by vaccination, but is also highly desirable for those infections where vaccination has not been implemented or did not fulfill its premises for complete protection., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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

The Holý Trinity was named after Dr Antonín Holý (the Holý Trinity being an Unesco recognized monument in Olomouc, Czech Republic), who together with Dr John C. Martin (Gilead Sciences) and myself pioneered a new class of antiviral agents, the acyclic nucleoside phosphonates. These compounds have revolutionized the antiviral drug field with several drugs that have been approved for the treatment of various DNA virus infections (cidofovir), hepatitis B (adefovir), and AIDS (HIV infection; tenofovir). The latter is also available as its oral prodrug, tenofovir disoproxil fumarate, for the treatment of hepatitis B and in combination with emtricitabine ((-)FTC) for the treatment and prophylaxis of HIV infections and in combination with (-)FTC and other HIV inhibitors, that is, efavirenz, rilpivirine, or elvitegravir (and a pharmacoenhancer thereof, cobicistat), for the treatment of AIDS., (© 2013 Elsevier Inc. All rights reserved.)

After a decade of having been the standard of care (SOC) for the treatment of chronic HCV infection, PEGylated IFN (combined with ribavirin) is now at the verge of being complemented and then replaced by a combination of new DAAs and even some compounds interacting with host cell factors. Principal targets for the direct-acting antivirals (DAAs) are the protease NS3/4A, the protein NS5A, and the RNA-dependent RNA polymerase NS5B, which offers at least two target sites, the catalytic domain for nucleos(t)ides and several non-catalytic (allosteric) domains for the non-nucleoside type of NS5B inhibitors. Two PIs have already been approved, but many more NS3/4A, NS5A, and NS5B (up to 40!) inhibitors are in (pre)clinical development. The abundance of candidate anti-HCV drugs will, on the one hand, speed up their development but, on the other hand, complicate the choice of the most appropriate drug combination(s)., (Copyright © 2012 John Wiley & Sons, Ltd.)

For the treatment of human immunodeficiency virus (HIV) infections for which there are ample drugs available, the immediate future lies in a once-daily combination pill containing three or four active ingredients. This strategy may also be envisaged for the treatment of hepatitis C virus (HCV) infections as soon as we have at hand the appropriate direct-acting antiviral agents (DAAs) to be combined. A combination drug therapy is generally not entertained for other viruses. Yet, new drugs are at the horizon for the treatment of herpes simplex virus (HSV), varicella-zoster virus (VZV), poxvirus, hepatitis B virus (HBV), influenza and enveloped viruses-at-large., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The configurations of metallocyclams are of interest in relation to protein recognition and anti-HIV activity. We have synthesised four novel zinc(II) complexes with hexyl-Me(2)-cyclam (HMC; 3,14-dimethyl-2,6,13,17-tetraazatricyclo(16.4.0.0(7,12))docosane), 1, and naphthyl-hexyl-Me(2)-cyclam (NHMC; 2,13-bis(1-naphthylmethyl)-5,16-dimethyl-2,6,13,17-tetraazatricyclo(16.4.0.0(7,12))docosane), 2, as ligands. X-ray crystallographic data for Zn(II)-HMC diacetate, 3 show that zinc is six-coordinate in a distorted octahedral environment bound to four equatorial N atoms from the macrocycle and two axial acetato O atoms. The 14-membered metallo-macrocycle adopts a trans-III (RRSS) configuration with two six-membered rings in chair forms and two five-membered rings in gauche forms. In the chlorido Zn(II)-HMC complex 5, zinc appears to be 5-coordinate with square-pyramidal geometry. Interestingly, the chlorido Zn(II)-NHMC complex 6 crystallised in a trans-I configuration containing 4-coordinate tetrahedral zinc bound to three cyclam ring N atoms, a possible model for intermediates formed during the uptake and release of metals by cyclams. The ligand 1 and the zinc complex 3 were active towards viral strains HIV-1 (III(B)) (IC(50) values of 10.51 ± 0.23 and 3.50 ± 0.33 μM, respectively), and HIV-2 (ROD) (IC(50) values of 133.78 ± 14.10 and >110.67 μM, respectively). 2D [(1)H, (13)C] and [(1)H, (15)N] NMR spectroscopic studies suggested that the types of configurational isomers present in solution depend on the axial ligand.

In continuation of our endeavor to develop new, potent, selective and less toxic antiviral agents, a novel series of 2-(2-amino/chloro-4-(2,4-dibromophenyl) thiazol-5-ylthio)acetamide derivatives was synthesized via an expeditious route and evaluated for their anti-HIV activities against wild-type virus and clinically relevant mutant strains, and for their anti-influenza virus activities against influenza A (H1N1 and H3N2) and influenza B in cellular assays. The selected active compounds were also assayed for their enzymic inhibitory activities. The results showed that some 2-chloro substituted thiazolylthioacetamide derivatives possessed potent activity against wild type HIV-1 and several key mutant strains (E138K, K103N, L100I) of HIV-1 in MT-4 cells with EC(50) values in micromolar range. Two 2-amino substituted thiazole derivatives 8a7 and 8a8 displayed significant potency against influenza A/H1N1 in MDCK cells with EC(50) values much lower than that of oseltamivir carboxylate, ribavirin, amantadine and rimantadine. Though the mechanism of actions is still unclear, these novel thiazolylthioacetamides might serve as original leads for further pharmacological investigations as potential therapeutic agents against HIV-1 or influenza virus.

Nucleoside and nucleotide analogues have proven to be an effective approach toward the development of antiviral compounds. This approach has so far yielded a number of clinically useful antiviral drugs, such as BVDU (brivudin), (val)aciclovir, cidofovir, adefovir dipivoxil, and tenofovir disoproxil fumarate, and current perspectives justify the further development of other nucleoside analogues, such as FV-100, and that of the DAPy-based nucleotide analogues, the 5-aza analogue of cidofovir, and prodrug derivatives thereof.

A series of novel dihydro-alkyloxy-benzyl-oxopyrimidine derivatives were synthesized and evaluated for their activity against influenza virus in Madin-Darby canine kidney cells. Four dihydro-alkyloxy-benzyl-oxopyrimidine derivatives (4a1, 4a2, 4a3, and 4d1) showed potent activity against influenza virus. Among them, compound 4a3 was the most promising lead with broad activity against influenza A (antiviral EC(50) values of 9 and 18 μm for the A/H1N1 and A/H3N2 subtype, respectively) and influenza B viruses (EC(50) : 33 μm). The antiviral mechanism of action of these dihydro-alkyloxy-benzyl-oxopyrimidine derivatives must be quite different from that of the currently approved anti-influenza virus drugs that target the viral M2 or neuraminidase proteins. The dihydro-alkyloxy-benzyl-oxopyrimidine derivatives represent a new avenue for further optimization and development of novel anti-influenza virus agents., (© 2011 John Wiley & Sons A/S.)

The use of the acyclic nucleoside phosphonates, starting with (S)-HPMPA as the prototype, yielded three clinically approved antiviral drugs, cidofovir for the treatment of CMV retinitis in AIDS patients, adefovir dipivoxil for the treatment of chronic hepatitis B and tenofovir disoproxil fumarate for the treatment of HIV infections (AIDS) and HBV infections. This era has now grown to many more acyclic (and cyclic) nucleoside phosphonates (such as the "open ring" DAPy and Fd4A phosphonates) and alkoxyalkyl and phosphonoamidate prodrugs thereof, as well as new clinical applications, including new drug combination regimens for the treatment of AIDS, the chemoprophylaxis of HIV infections, and the anticancer potential against some malignant disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)

About 3% of world's population is infected by the hepatitis C virus (HCV), for which prophylactic vaccine is not available yet. Nowadays, pegylated interferon-α and ribavirin are commonly used to treat HCV; unfortunately these drugs often produce significant side effects. Upon the desperate need of anti-HCV drugs, a plan to establish a new compound library was set that included leads with high antiviral activity, good hydrophilicity, yet low toxicity. Accordingly, 26 new conjugated compounds were synthesized through the chemical coupling of various 9-(β-D-ribofuranosyl)purine-8-thiones with 3-(chloromethyl)coumarins bearing various substituents. A -SCH(2)- unit was used to link the coumarin and the purine moieties. The three hydroxyl groups at the 2'-, 3'-, and 5'-positions were selectively protected with an acyl or acetal group in these coumarin-purine ribofuranosides. Their anti-HCV and cytostatic determination assays were performed, and the structure-activity relationship was established. Three conjugates in the family of 8-(coumarin-3'-yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine possessed an appealing ability to inhibit HCV replication with EC(50) between 5.5 and 6.6 μM and EC(90) of ∼20 μM. These data in the new compound library provide clues for the future in the development of anti-HCV leads for viral eradication.

This review article presents the fifth part (part E) in the series of stories on antiviral drug discovery. The ten stories belonging to this fifth part are dealing with (i) aurintricarboxylic acid; (ii) alkenyldiarylmethanes; (iii) human immunodeficiency virus (HIV) integrase inhibitors; (iv) lens epithelium-derived growth factor as a potential target for HIV proviral DNA integration; (v) the status presens of neuraminidase inhibitors NAIs in the control of influenza virus infections; (vi) the status presens on respiratory syncytial virus inhibitors; (vii) tricyclic (1,N-2-ethenoguanine)-based acyclovir and ganciclovir derivatives; (viii) glycopeptide antibiotics as antivirals targeted at viral entry; (ix) the potential (off-label) use of cidofovir in the treatment of polyoma (JC and BK) virus infections; and (x) finally, thymidine phosphorylase as a target for both antiviral and anticancer agents., (© 2009 Wiley Periodicals, Inc.)