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Antiviral Research (v.67, #2)
Antiviral drug discovery and development: Where chemistry meets with biomedicine by Erik De Clercq (pp. 56-75).
The successful development of antiviral drugs is highly dependent on a close interaction and collaboration between the chemist and the biologist (biomedic). This is illustrated by a number of representative examples: S-adenosylhomocysteine (SAH) hydrolase inhibitors which display broad-spectrum antiviral activity, bromovinyldeoxyuridine (BVDU) and derivatives thereof, that are highly selective inhibitors of varicella-zoster virus (VZV), (dideoxy)nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are now widely used in the treatment of HIV infections (AIDS), the bicyclams (i.e. AMD3100) which were originally discovered as anti-HIV agents, then found to be potent CXCR4 antagonists and now being pursued for a number of indications such as stem cell mobilization, and the acyclic nucleoside phosphonates which have heralded a new strategy for the treatment of various DNA virus (herpes-, adeno-, pox-, papillomavirus) infections (cidofovir), hepatitis B (adefovir) and AIDS (tenofovir).
Keywords: Antivirals; HIV (AIDS); HBV (Hepatitis B); HSVC (Herpes Simplex); VZV (Herpes Zoster); DNA viruses
Screening for hepatitis C virus antiviral activity with a cell-based secreted alkaline phosphatase reporter replicon system by Nigel Bourne; Richard B. Pyles; MinKyung Yi; Ronald L. Veselenak; Melissa M. Davis; Stanley M. Lemon (pp. 76-82).
We describe a phased screening system for discovery of compounds with antiviral activity against hepatitis C virus (HCV). The primary assay utilizes dicistronic subgenomic HCV replicons in which the upstream cistron was modified to express the human immunodeficiency virus (HIV) tat protein. When these replicons are stably transfected into Huh-7-derived cells that express secreted alkaline phosphatase (SEAP) under transcriptional control of the HIV long terminal repeat promoter, there is a strong correlation between intracellular HCV RNA abundance and the activity of SEAP secreted into the culture medium. Thus, active compounds are easily identified by direct enzymatic quantification of SEAP in the medium without post-assay processing. Compounds that reduce SEAP activity without causing cellular toxicity are next evaluated in a second Huh-7-derived cell line constitutively expressing SEAP under control of the tat-HIV promoter axis, independent of HCV RNA replication. This specificity control identifies compounds that cause reductions in SEAP that are unrelated to suppression of HCV RNA replication. Compounds showing HCV-specific activity in primary assays are next evaluated by real-time RT-PCR to directly quantify reductions in HCV RNA. We have found excellent agreement between the SEAP and RT-PCR assays. This phased system provides an efficient and cost-effective screen for compounds with antiviral activity against HCV.
Keywords: Hepatitis C virus; Antiviral activity; Alkaline phosphatase
Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA) by Maria T. Polianova; Francis W. Ruscetti; Candace B. Pert; Michael R. Ruff (pp. 83-92).
The chemokine receptor CCR5 plays a crucial role in transmission of HIV isolates, which predominate in the early and middle stages of infection, as well as those, which populate the brain and cause neuro-AIDS. CCR5 is therefore an attractive therapeutic target for design of entry inhibitors. Specific rapid filtration binding assays have been useful for almost 30 years both for drug discovery and understanding molecular mechanisms of drug action. Reported in 1986, prior to discovery of chemokine co-receptors and so thought to act at CD4, peptide T (DAPTA) appears to greatly reduce cellular viral reservoirs in both HAART experienced and treatment naïve patients, without toxicities. We here report that DAPTA potently inhibits specific CD4-dependent binding of gp120 Bal (IC50=0.06nM) and CM235 (IC50=0.32nM) to CCR5. In co-immunoprecipitation studies, DAPTA (1nM) blocks formation of the gp120/sCD4 complex with CCR5. Confocal microscopic studies of direct FITC–DAPTA binding to CCR5+, but not CCR5−, cells show that CCR5 is a DAPTA receptor. The capability of DAPTA to potently block gp120–CD4 binding to the major co-receptor CCR5 explains its molecular and therapeutic mechanism of action as a selective antiviral entry inhibitor for R5 tropic HIV-1 isolates.
Keywords: Envelope; gp120; Binding; CCR5; Chemokine; Receptor; HIV-1; Entry; Treatments
Polymorphisms in the interferon-γ gene at position +874 in patients with chronic hepatitis C treated with high-dose interferon-α and ribavirin by Chia-Yen Dai; Wan-Long Chuang; Wen-Yu Chang; Shinn-Cherng Chen; Li-Po Lee; Ming-Yen Hsieh; Nei-Jen Hou; Zu-Yau Lin; Ming-Yuh Hsieh; Liang-Yen Wang; Ming-Lung Yu (pp. 93-97).
To investigate the influence of the T-to-A polymorphic sequence at position +874 in the interferon (IFN)-γ gene (+874 IFN-γ) on the response to combination therapy with high-dose interferon and ribavirin, the single nucleotide polymorphisms were determined by using a polymerase chain reaction sequence-specific primers approach in 150 histologically proved chronic hepatitis C (CHC) patients. The distribution of genotypes for +874 IFN-γ were T/T: 6 (4.0%), T/A: 31 (20.7%) and A/A: 113 (75.3%) and 24.7% (37/150) of patients were inherited T allele. After undergoing combination therapy with high-dose IFN-α and ribavirin, 70.7% (106/150) of patients achieved sustained viral response (SVR). Based on multivariate regression analyses, the independent factors predicting HCV SVR after combination therapy were HCV genotype non-1b ( P<0.001) and low pretreatment HCV RNA levels ( P=0.041) (odds ratios/95% C.I.: 10.150/4.023–25.609 and 0.581/0.345–0.979, respectively). No association between genotypes, A or T alleles of +874 IFN-γ and response to combination therapy with high-dose IFN-α and ribavirin.In conclusion, we found that with high SVR rates after combination therapy with high-dose IFN-α and ribavirin, HCV genotypes and pretreatment serum HCV RNA levels, but not inheritance of the IFN-γ polymorphism at the position +847, were predictors for SVR.
Keywords: Combination therapy; Hepatitis C virus; IFN-α; IFN-γ; Polymorphism; Ribavirin
Ion transport blockers inhibit human rhinovirus 2 release by Elena V. Gazina; David N. Harrison; Meryem Jefferies; Heneu Tan; David Williams; David A. Anderson; Steven Petrou (pp. 98-106).
Picornavirus replication causes leakage of cytoplasmic K+ and an influx of Na+ and Ca2+. In this study, we have explored the possibility that a blockade of Ca2+ and Na+ influx would reduce rhinovirus production and/or release. The Ca2+-channel blockers, verapamil and diltiazem, as well as the blocker of Na+/H+ exchange and the epithelial Na+ channel, EIPA, inhibited both virus production and release. The effect on virus release was more pronounced than the effect on production, thus raising the possibility that rhinovirus release may serve as a target for antiviral agents. Unexpectedly, our results also showed that the antiviral activity of the Ca2+-channel blockers was not due to the block of Ca2+ influx. Similarly, the antiviral activity of EIPA appeared to be unrelated to the blockade of cellular Na+/H+ exchanger or the epithelial Na+ channel. Potential alternative mechanisms of the antiviral activity of these compounds are discussed.
Keywords: Ion transport blockers; Rhinovirus
Extracts and molecules from medicinal plants against herpes simplex viruses by Mahmud Tareq Hassan Khan; Arjumand Ather; Kenneth D. Thompson; Roberto Gambari (pp. 107-119).
Herpes simplex viruses (HSV-1 and -2) are important pathogens for humans, especially in the case of highly susceptible adults. Moreover, HSV-2 has been reported to be a high risk factor for HIV infection. Therefore, the discovery of novel anti-HSV drugs deserves great efforts. In this paper, we review anti-HSV substances from natural sources, including both extracts and pure compounds from herbal medicines, reported in studies from several laboratories. The role of traditional medicine for the development of anti-HSV compounds is also discussed. Interestingly, it was found that traditional medicines, like Ayurvedic, traditional Chinese (TCM), Chakma medicines, are good and potential sources for promising anti-HSV drugs. A second objective of this review is to discuss several anti-HSV compounds with respect to their structure–activity relationship (SAR). A large number of small molecules, like phenolics, polyphenols, terpenes (e.g., mono-, di-, tri-), flavonoids, sugar-containing compounds, were found to be promising anti-herpetic agents. Our major conclusion is that natural products from medicinal plant extracts are very important source of anti-HSV agents.
Keywords: Abbreviations; ACV; acyclovir; ACV-R; acyclovir-resistant; ACV-S; acyclovir susceptible; ADMET; absorption distribution metabolism, excretion and toxicity; AIDS; acquired immune-deficiency syndrome; CC; 50; median cytotoxic concentration; CPE; cytopathic effect; EC; 50; median effective concentration; ED; 50; median effective dose; EPTT; end-point titration technique; GC/MS; gas chromatography/mass spectrometry; GFS; galactofucan; HIV; human immunodeficiency virus; HSV; herpes simplex viruses; IC50; median inhibitory concentration; MIC; minimal inhibition concentration; MTT; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PB233′OG; prodelphinidin B-2 3,3′-di-O-gallate; PF; polysaccharide fraction; PPV; Prunella vulgaris; SAR; structure–activity relationship; SI; selectivity index; STD; sexually transmitted diseases; TCM; traditional Chinese medicine; TI; therapeutic index; TK; thymidine kinase; VSV; vesicular stomatitis virus; XTT; tetrazolium salt (2,3-bis(2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide)Herpes simplex viruses; Herbal medicine; Acyclovir; Famciclovir; Acyclovir-resistance; Antiviral; Anti-HSV; Chakma Talika Chikitsa; Structure–activity relationship; Ethnomedicine; Traditional medicine