Showing papers in "Antiviral Chemistry & Chemotherapy in 2009"
TL;DR: This review identifies many understudied areas of research, along with topics for further research in the field of HIV therapy and eradication, and focuses upon the known cellular pharmacology and antiviral activity of antiretroviral agents in macrophages and its relationship to latency, chronic HIV-1 infection and therapeutic strategies to eradicate systemic HIV- 1 infection.
Abstract: HIV type-1 (HIV-1) accounts for more than 25 million deaths and nearly 40 million people are infected worldwide. A significant obstacle in clearing virus from infected individuals is latently infected viral reservoirs. Latent HIV-1 can emerge with recrudescence as a productive infection later in disease progression and could provide a source for the emergence of resistant HIV-1. It is widely recognized that macrophages represent a latently infected viral reservoir and are a significant and critical HIV-1 target cell in vivo. Macrophages can be divided into multiple subsets of macrophage-like cells, all of which are susceptible to HIV-1 infection, including dendritic cells, Langerhans cells, alveolar macrophages, mucosal macrophages and microglial cells. Current antiretroviral therapy (ART) often displays differential antiviral activity in macrophages relative to CD4(+) T-lymphocytes. Significant work has been performed to establish antiviral activity of many clinically approved ART in macrophages; however, a direct link between antiviral activity and specific mechanisms responsible for these antiviral effects are incompletely understood. This review identifies many understudied areas of research, along with topics for further research in the field of HIV therapy and eradication. Discussion focuses upon the known cellular pharmacology and antiviral activity of antiretroviral agents in macrophages and its relationship to latency, chronic HIV-1 infection and therapeutic strategies to eradicate systemic HIV-1 infection.
86 citations
TL;DR: Once-daily administration of elvitegravir has a comparable antiviral activity to twice-daily of raltegravIR in HIV-1-infected patients.
Abstract: Integration is a distinctive and essential process in the HIV infection cycle and thus represents an attractive antiviral drug target. Integrase inhibitors combined with other classes of drug might contribute to long-lasting suppression of HIV type-1 (HIV-1) replication for many patients. Of the numerous potential integrase inhibitor leads that have been reported, few have reached clinical trials and only one, raltegravir, has been approved (in late 2007) for the treatment of HIV-1-infected patients. Another integrase inhibitor, elvitegravir, is currently showing promise in Phase III clinical studies. Once-daily administration of elvitegravir has a comparable antiviral activity to twice-daily of raltegravir in HIV-1-infected patients. Here, we highlight the salient features of elvitegravir: its chemical structure compared with representative integrase inhibitors, mechanism of action, in vitro and in vivo activity against HIV and other retroviruses, and the effect of integrase polymorphisms and resistance mutations on its anti-HIV activity.
83 citations
TL;DR: The best docking score and binding energy for 6 MP and 6TG is against ubiquitin-specific protease (USP)14, suggesting that 6MP and 6 TG are potential inhibitors of USP14.
Abstract: In the search for effective therapeutics against severe acute respiratory syndrome (SARS), 6-mercaptopurine (6MP) and 6-thioguanine (6TG) were found to be specific inhibitors for the SARS—coronavirus (CoV) papain-like protease (PLpro), a cysteine protease with deubiquitinating and deISGylating activity. 6MP and 6TG have long been used in cancer chemotherapy for treatment of acute lymphoblastic or myeloblastic leukaemia. Development and optimization of 6MP and 6TG will not only be important for anti-viral studies, but also for further elucidating the biological functions of cellular deubiquitinating enzymes (DUBs) and deISGylating enzymes. So far, several crystal structures of cellular DUBs have been solved. Structure comparison has been carried out to search for DUBs with a similar structure to that of PLpro, and we have tried to dock 6MP and 6TG into these DUBs to investigate the potential use of 6MP and 6TG as cellular DUB inhibitors. The best docking score and binding energy for 6MP and 6TG is against ...
72 citations
TL;DR: New information and essential lessons have emerged for the field, and there are reasons for renewed confidence that a safe and effective microbicide is achievable.
Abstract: HIV microbicides are topical, self-administered products aimed at preventing or reducing HIV infection in women and may represent the most promising strategy for combating the HIV/AIDS epidemic at the present time. Although a safe and effective microbicide has yet to be identified, all products tested in Phase III trials to date have been vaginal gels containing non-specific compounds with modest potency that had to be applied close to the time of sexual intercourse. Issues regarding these early generation products were further complicated by widely publicized cases of halted efficacy trials. However, as a result of each of these challenges, new information and essential lessons have emerged for the field. These lessons have resulted in a meaningful increase in microbicide development efforts focusing on compounds with highly potent and HIV-specific mechanisms of action, combination products, novel formulations, and carefully designed pharmacokinetic and pharmacodynamic evaluations, all of which are reasons for renewed confidence that a safe and effective microbicide is achievable.
66 citations
TL;DR: The degree of sulfation seemed to play an important role because desulfation and/or further sulfation of the isolated macromolecules largely influenced their in vitro anti-HSV-1 activity.
Abstract: Background:Many viruses display affinity for cell surface heparan sulfate proteoglycans with biological relevance in virus entry. This raises the possibility of the application of sulfated polysaccharides in antiviral therapy.Methods:In this study, we analysed polysaccharide fractions isolated from Sebdenia polydactyla.Results:The purified xylomannan sulfate and its further sulfated derivatives showed strong activity against herpes simplex virus type-1 (HSV-1). Their 50% inhibitory concentration values were in the range 0.35–2.8 µg/ml and they lacked cytotoxicity at concentrations up to 1,000 µg/ml. The major polysaccharide, which had 0.6 sulfate groups per monomer unit and an apparent molecular mass of 150 kDa, contained a backbone of α-(1→3)-linked D-mannopyranosyl residues substituted at position 6 with a single stub of s-D-xylopyranosyl residues.Conclusions:The degree of sulfation seemed to play an important role because desulfation and/or further sulfation of the isolated macromolecules largely influ...
56 citations
TL;DR: This study identified ATA as a potent anti- NS5B inhibitor and suggests that its unique mode of action might be exploited for structural refinement and development of novel anti-NS5B agents.
Abstract: Background:Hepatitis C virus (HCV) NS5B is an essential component of the viral replication machinery and an important target for antiviral intervention. Aurintricarboxylic acid (ATA), a broad-spectrum antiviral agent, was evaluated and characterized for its anti-NS5B activity in vitro and in HCV replicon cells.Methods:Recombinant NS5B, HCV replicase and Huh-7 cells harbouring the subgenomic HCV replicon of genotype 1b were employed for biochemical and mechanistic investigations.Results:Analysis of ATA activity in vitro yielded equipotent inhibition of recombinant NS5B and HCV replicase in the submicromolar range (50% inhibition concentration [IC50] approximately 150 nM). Biochemical and mechanistic studies revealed a bimodal mechanism of ATA inhibition with characteristics of pyrophosphate mimics and non-nucleoside inhibitors. Molecular modelling and competition displacement studies were consistent with these parameters, suggesting that ATA might bind to the benzothiadiazine allosteric pocket 3 of NS5B or...
41 citations
TL;DR: In the past years, large numbers of promising fusion inhibitory peptides have emerged and some of these new compounds have great potential to be further developed as therapeutic agents.
Abstract: There are now 26 antiretroviral drugs and 6 fixed-dose combinations, including reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and fusion (or entry) inhibitors, approved by the US Food and Drug Administration for clinical use. Although they are clinically effective when used in combination, none of the existing drugs are considered ideal because of toxic side effects and the ascendance of inducing drug-resistant mutants. Development of new antiviral agents is essential. In the past decades, there has been great progress in understanding the structure of HIV type-1 (HIV-1) gp41 and the mechanism of HIV-1 entry into host cells. This opened up a promising avenue for rationally designed agents to interfere with this process. A number of fusion inhibitors have been developed to block HIV-1 replication. Enfuvirtide (T20) was one of those approved for clinical use. This signalled a new era in AIDS therapeutics. It is a synthetic polypeptide with potent inhibitory activity against HIV-1 infection. However, it is sensitive to proteolytic digestion and resistant virus strains are easily induced with multiple clinical use. One of the directions in designing new fusion inhibitors is to overcome these shortages. In the past years, large numbers of promising fusion inhibitory peptides have emerged. The antiviral activities are more potent or they can act differently from that of T20. Some of these new compounds have great potential to be further developed as therapeutic agents. This article reviewed some recent developments of these peptides and the possible role in anti-HIV-1 therapy.
40 citations
TL;DR: Optimized elderberry, green tea and cinnamon extracts rich in certain flavonoid compounds were shown to block HIV-1 entry and infection in GHOST cells, suggesting these types of botanical extracts could provide a starting point for the development of possible safe and reliable cotherapies for HIV- 1-positive individuals.
Abstract: Background:The development of antiviral drugs has provided crucial new means to mitigate or relieve the debilitating effects of many viral pathogens. Regular use of these drugs has led to generation of resistant strains, making the control of many viral infections very difficult, particularly in HIV-seropositive and AIDS patients. A rich source for the discovery of new HIV infection inhibitors has been, and continues to be, the ‘mining’ of the large diversity of compounds already available in nature, and specifically those from botanical extracts.Methods:Using a newly developed direct binding assay with mass spectrometry technology (direct analysis in real-time time-of-flight mass spectrometry), we were able to show that compounds present in extracts of elderberry, cinnamon and green tea bind to and block HIV type-1 (HIV-1) infection in target cells.Results:The compounds that blocked HIV-1 infection were flavonoids and A-type proanthocyanidins. The 50% inhibitory concentration values of these extracts ran...
35 citations
TL;DR: The combination of TFV with FTC, 3TC, ETV, LdT or AFV had additive to slightly synergistic anti-HBV effects in vitro, which support the use of TDF as a component in combination regimens with currently available anti- HBV nucleoside analogues.
Abstract: Background:Long-term management of some chronic hepatitis B patients might require combination therapy using drugs with distinct resistance profiles to sustain viral suppression and to reduce the resistance-associated failure. Tenofovir disoproxil fumarate (TDF), approved for hepatitis B virus (HBV) and HIV-1 treatment, is active against wild-type HBV and HBV containing YMDD mutations, which confer resistance to emtricitabine (FTC), lamivudine (3TC) and telbivudine (LdT) and contribute to entecavir (ETV) resistance. We therefore evaluated the in vitro anti-HBV activity of tenofovir (TFV), the active parent drug of TDF, combined with FTC, 3TC, ETV, LdT and adefovir (AFV).Methods:The anti-HBV activities of the compounds were tested using the AD38 cell line that expresses wild-type HBV from a tetracycline-controllable promoter. Intracellular HBV DNA levels were quantified using real-time PCR assay and cytotoxicities were assessed with XTT assays. The antiviral data of the drug combinations were evaluated usi...
28 citations
TL;DR: This work is the first example of both inactive uridine and cytidine analogues of a nucleoside being converted to active anti-HCV nucleosides via 5′-monophosphate prodrugs.
Abstract: Background:2′-C-methyl and 4′-azido nucleosides have previously demonstrated inhibition of hepatitis C virus (HCV) replication by targeting the RNA-dependent RNA polymerase NS5B In an effort to di
26 citations
TL;DR: This review provides an overview and a summary of the current status of drug development in the field of HIV type-1 replication by highly active anti-retroviral therapy.
Abstract: Despite the recent licensure of several new antiretroviral compounds, there is still a need to develop additional agents. Problems with antiviral activity, tolerability, ease of administration, extent of cross-resistance and pharmacokinetic as well as pharmacodynamic interactions still represent important obstacles to life-long control of HIV type-1 replication by highly active antiretroviral therapy. Several compounds stem from the same classes as currently available drugs: apricitabine and elvucitabine (nucleoside reverse transcriptase inhibitors), rilpivirine (non-nucleoside reverse transcriptase inhibitor), vicriviroc and INCB009471 (CCR5 inhibitors) and elvitegravir (integrase inhibitor). The potential of other compounds with new modes of action is less clear. Currently, maturation inhibitors appear promising but for other drugs, obstacles to continued development, such as the need of parenteral application (that is, monoclonal antibodies) or toxicity (for example, immune modulating agents and pegylated interferon), are already apparent. For even more compounds in the preclinical development phase, an assessment of their possible clinical role is still premature. This review provides an overview and a summary of the current status of drug development in the field.
TL;DR: The prodrug valcyclopropavir offers some improved therapeutic parameters over the parent compound cyclopropaviral nucleoside analogues.
Abstract: Background:Following the example of L-valine prodrugs of antiviral nucleoside analogues, L-valine ester of cyclopropavir (valcyclopropavir) was synthesized.Methods:The known tetrahydropyranylcyclop...
TL;DR: 5-chlorophenyl-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560) was the most active against BVDV, and its 50% effective and cytotoxic concentrations were 10.9 ±2.8 and 93.5 μM in virus and mock-infected MDBK cells, respectively.
Abstract: Background: A number of compounds were examined for their inhibitory effect on bovine viral diarrhoea virus (BVDV) replication in cell cultures and found that some cyclooxygenase (COX) inhibitors had antiviral activity against the virus. Methods: Determination of compounds for their anti-BVDV activity was on the basis of the inhibition of virus-induced cytopathogenicity in Mardin–Darby bovine kidney (MDBK) cells. Anti-hepatitis C virus (HCV) activity was assessed by the inhibition of viral RNA synthesis in the subgenomic HCV RNA replicon cells. Results: Among the test compounds, 5-(4-chlorophenyl)1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H -pyrazole (SC-560) was the most active against BVDV, and its 50% effective and cytotoxic concentrations were 10.9 ±2.8 and 93.9 ±24.5 µM in virus and mock-infected MDBK cells, respectively. The compound also suppressed BVDV RNA synthesis in a dose-dependent fashion. Studies on the mechanism of action revealed that SC-560 did not interfere with viral entry to the host cells. Furthermore, it was assumed that the antiviral activity of SC-560 was not associated with its inhibitory effect on COX. The combination of SC-560 and interferon-α was additive to synergistic in inhibiting BVDV replication. More importantly, the compound proved to be a selective inhibitor of HCV replication. Conclusions: SC-560 and its derivative might have potential as novel antiviral agents against HCV.
TL;DR: This in vitro study demonstrated for the first time that ganciclovir exhibited an in vitro duration-dependent toxicity on haematopoietic-derived cells when in vivo doses of the drug were used.
Abstract: Introduction:Human cytomegalovirus infection is still a major complication after pediatric bone marrow transplantation and could be fatal in some cases. The toxicity of the drug in dividing transplanted haematopoietic cells combined with the suppression of cell growth caused by the virus remains a major problem in managing human cytomegalovirus infection.Methods:The aim of the current in vitro study was to evaluate the effect of the intensity (1–20 mg/l) and duration (1, 2, 7 or 14 days) of ganciclovir exposure on toxicity in B lymphoblastoid cells (using cell counting and viability measurements).Results:A correlation was found between the dose of ganciclovir exposure and a decrease in total cell number when duration exceeded 2 days (r2=0.92 and 0.93 after 7 and 14 days, respectively). High levels (20 mg/l) of ganciclovir were not more toxic than lowest levels (1 mg/l) for the shortest durations of ganciclovir exposure (1 and 2 days). Moreover, 50% cytotoxic concentrations markedly decreased with the dura...
TL;DR: This review article focuses on the basic principles of an RNAi-based gene therapy against HIV-1, including delivery methods, target selection, viral escape possibilities, systems for multiplexing siRNAs to achieve a durable therapy and the in vitro and in vivo test systems to evaluate the efficacy and safety of such a therapy.
Abstract: RNA interference (RNAi) is a cellular mechanism that can be induced by small interfering RNAs (siRNAs) to mediate sequence-specific gene silencing by cleavage of the targeted messenger RNA. RNAi can be used as an antiviral approach to silence HIV type-1 (HIV-1) through stable expression of precursors, such as short hairpin RNAs (shRNAs), which are processed into siRNAs that can elicit degradation of HIV-1 RNAs. At the beginning of 2008, the first clinical trial using a lentivirus with an RNA-based gene therapy against HIV-1 was initiated. The antiviral molecules in this gene therapy consist of three RNA effectors, one of which triggers the RNAi pathway. This review article focuses on the basic principles of an RNAi-based gene therapy against HIV-1, including delivery methods, target selection, viral escape possibilities, systems for multiplexing siRNAs to achieve a durable therapy and the in vitro and in vivo test systems to evaluate the efficacy and safety of such a therapy.
TL;DR: Dextran-propan-1,3-diamine (DPD) was found to be the most potent of all the compounds examined and could have an advantage as a topical application in combination therapy of HSV lesions.
Abstract: Background:Herpes simplex virus (HSV) establishes latent infection in humans with periodic reactivation. Acyclovir, valacyclovir and foscarnet are in medical use today against HSV type-1 (HSV-1) an...
TL;DR: The current knowledge regarding the mechanisms underlying maintenance of HIV-1 latency is reviewed, both transcriptional and post-transcriptional, with a focus on potential targets that might be exploited to therapeutically purge latent proviral reservoirs from infected patients.
Abstract: HIV type-1 (HIV-1) can establish a state of latency in infected patients, most notably in resting CD4 + T-cells. This long-lived reservoir allows for rapid re-emergence of viraemia upon cessation of highly active antiretroviral therapy, even after extensive and seemingly effective treatment. Successful depletion of such latent reservoirs is probably essential to 'cure' HIV-1 infection and will require therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. The mechanisms underlying HIV-1 latency are not well characterized, and it is becoming clear that numerous factors, both cell- and virus-derived, are involved in the maintenance of proviral latency. The interplay of these various factors in the context of viral reactivation is still poorly understood. In this article, we review the current knowledge regarding the mechanisms underlying maintenance of HIV-1 latency, both transcriptional and post-transcriptional, with a focus on potential targets that might be exploited to therapeutically purge latent proviral reservoirs from infected patients.
TL;DR: A preliminary assessment of a small group of related analogues was unsuccessful, but further screening of this class of compounds is warranted as a large class of potential inhibitors of the influenza virus polymerase.
Abstract: Background:An unusual feature of influenza viral messenger RNA (mRNA) synthesis is its dependence upon host cell mRNAs as a source of capped RNA primers. A crucial activity of the influenza polymerase is to steal these primers by binding and cleaving the caps from host mRNAs. The recent structural analysis of the cap-binding fragment of the influenza virus PB2 protein has highlighted the importance of the mesoionic properties of the N7-methylguanine (N7mG) component of the mRNA cap in this interaction.Methods:A series of mesoionic heterocycles with 5,6-fused ring systems analogous to the N7mG component of mRNA cap structures were synthesized and examined for the ability to inhibit the cap-binding activity of the influenza virus RNA polymerase complex using a bead-based in vitro cap-binding assay.Results:None of the compounds tested were able to significantly inhibit binding and subsequent endonucleolytic cleavage of a synthetic radiolabelled capped mRNA substrate by recombinant influenza virus polymerase ...
TL;DR: Investigation of HIV RNA and HIV DNA levels with an INI will provide better understanding of how these components are generated and maintained under antiretroviral therapy.
Abstract: The integrase inhibitor (INI) raltegravir has shown promising results in clinical trials to date, reducing second phase HIV RNA levels by 70% in comparison with standard regimens. These trial results have been limited by the 50 copies/ml detection limit of the HIV RNA assay and have not investigated the effect of an INI regimen on levels of latently infected cells. Mathematical models that duplicated previous raltegravir results were extended to estimate effects of an INI regimen on HIV RNA beyond second phase and on HIV DNA levels. Depending on assumptions underlying later phase HIV RNA generation and its interaction with latently infected cells, HIV RNA in later phases can be lower or show no difference with an INI, and similarly for HIV DNA. If latent infection is maintained by differentiation of stem cells with integrated HIV DNA, then an INI regimen will eventually have no added benefit. Other hypotheses that allow ongoing replication predict continually lower HIV RNA levels with an INI regimen, but this differential effect need not translate to a reduction in latent infection. Investigation of HIV RNA and HIV DNA levels with an INI will provide better understanding of how these components are generated and maintained under antiretroviral therapy.
TL;DR: Antiviral evaluation revealed that none of these analogues showed inhibitory activity against a wide variety of DNA and RNA viruses, suggesting that conformational difference of the sugar moiety of 8a-1 from that of xylo-A could be attributable to their inactivity.
Abstract: BACKGROUND Motivated by the reported biological activity of 9-(beta-D-xylofuranosyl)adenine (xylo-A), the synthesis of its 4'-alkoxy analogues was carried out. METHODS The starting material 9-(3-deoxy-beta-D-glycero-pento-3-enofuranosyl)adenine (1) was prepared from adenosine. Compound 1 was converted to the 2',5'-bis-O-(tert-butyldimethylsilyl) derivative (2) and then to the N(6)-pivaloyl derivative (3). When 3 was reacted with meta-chloroperbenzoic acid in the presence of a series of alcohols, the beta-D-isomer of the respective 4'-alkoxy derivative was obtained exclusively in high yield. Deprotection of these products led to the isolation of the desired 4'alkoxy analogues (8a-l) of xylo-A. RESULTS Antiviral evaluation revealed that none of these analogues showed inhibitory activity against a wide variety of DNA and RNA viruses. CONCLUSIONS We assume that conformational difference of the sugar moiety of 8a-l from that of xylo-A could be attributable to their inactivity.