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Antiviral Research (v.65, #2)

Inside Back Cover: Notes to Authors (pp. co3).

Inside Front Cover: Editorial Board (pp. co2).

Prevention of HIV-1 infection by platinum triazines by A.N. Vzorov; D. Bhattacharyya; L.G. Marzilli; R.W. Compans (pp. 57-67).

To identify and explore the activity of compounds which may act as anti-HIV virucidal agents, we have investigated platinum compounds, especially those containing N-donor aromatic ligands. After screening over 70 related agents, including N-donor aromatic ligands and metal precursors, we have identified a novel class of platinum(II) complexes with 2-pyridyl-1,2,4-triazine derivatives and Pt(II) formulations with these derivatives (ptt compounds) as having the highest anti-HIV activity. The maximum activity was observed when the agents were added immediately post-infection. The ptt agents did not block cell fusion activity of HIV-1 Env proteins in cells bearing CD4X4 or CD4R5 receptors, indicating a lack of interaction with the Env protein. The ptt compounds exhibit low toxicity for human epithelial cells, and are thus promising candidates for use as microbicides or antiviral agents against HIV.

Keywords: HIV; Microbicides; Reverse transcriptase inhibitor

Characterization of viral proteins encoded by the SARS-coronavirus genome by Yee-Joo Tan; Seng Gee Lim; Wanjin Hong (pp. 69-78).

A new disease, termed severe acute respiratory syndrome (SARS), emerged at the end of 2002 and caused profound disturbances in over 30 countries worldwide in 2003. A novel coronavirus was identified as the aetiological agent of SARS and the 30kb viral genome was deciphered with unprecedented speed in a coordinated manner by the global community. Since then, much progress has been made in the virological and molecular characterization of the proteins encoded by SARS-coronavirus (SARS-CoV) genome, which contains 14 potential open reading frames (ORFs). These investigations can be broadly classified into three groups: (a) studies on the replicase 1a/ 1b gene products which are important for viral replication, (b) studies on the structural proteins, spike, nucleocapsid, membrane and envelope, which have homologues in all coronaviruses, and are important for viral assembly and (c) expression and functional studies of the “accessory�? proteins that are specifically encoded by SARS-CoV. A comparison of the properties of these three groups of SARS-CoV proteins with the knowledge that coronavirologists have generated over more than 30 years of research can help us in the prevention and treatment of SARS in the event of the re-emergence of this new infectious disease.

Keywords: Severe acute respiratory syndrome (SARS); Coronavirus; Viral proteins

Treatment of West Nile virus-infected mice with reactive immunoglobulin reduces fetal titers and increases dam survival by Justin G. Julander; Quinton A. Winger; Aaron L. Olsen; Craig W. Day; Robert W. Sidwell; John D. Morrey (pp. 79-85).

The objectives of this study were to determine if injection of West Nile virus (WNV) into timed-pregnant mice would result in fetal infection and if administration of WNV-reactive immunoglobulin would increase dam survival and reduce fetal viral titers. Dams injected on 7.5 days post-coitus (dpc) had detectable viral titers in the placenta 10.5dpc with a mean titer of 10^4.9 50% cell-culture infectious doses per gram of tissue (CCID₅₀/g tissue). The mean placental titer increased to 10^8.6CCID₅₀/g tissue at 12.5dpc. Infectious virus was detectable 12.5dpc in 10 of 10 fetuses with a mean titer of 10^7.5CCID₅₀/g tissue. Treatment of dams (challenged with WNV on 7.5dpc) with WNV-reactive human immunoglobulin (Ig) on 8.5 and 9.5dpc resulted in a significant reduction of virus in fetuses as compared with non-reactive human Ig-treated females on 12.5dpc ( P≤0.001). Treatment also resulted in survival of dams to term. Treatment of dams with WNV-reactive human Ig on 12.5 and 13.5dpc also resulted in reduction of viral titer on 14.5dpc, indicating that later treatment may also be efficacious. This suggests that Ig treatment may be useful in treating fetal WNV infection in women.

Keywords: West Nile virus; Pregnancy; Fetus; Placenta; Immunoglobulin therapy; Flavivirus

CpG-DNA protects against a lethal orthopoxvirus infection in a murine model by D.G. Cerys Rees; Amanda J. Gates; Michael Green; Lin Eastaugh; Roman A. Lukaszewski; Kate F. Griffin; Arthur M. Krieg; Richard W. Titball (pp. 87-95).

CpG-DNA has been described as a potent activator of the innate immune system, with potential to protect against infection caused by a range of pathogens in a non-specific manner. Here two classes of CpG-DNA (CpG-A and CpG-B) have been investigated for their abilities to protect mice from infection with an orthopoxvirus (vaccinia virus). Dosing with either CpG-A or B by the intraperitonal or intranasal route protected mice against a subsequent intranasal challenge with vaccinia virus. To our knowledge, this is the first time CpG-mediated protection has been demonstrated at the lung surface. The level of protection was greater when CpG-DNA was administered intranasally demonstrating a clear relationship between the route of CpG dosing and infection route. Treatment with CpG-B reduced viral titer in the lung by 10,000-fold at day 3 post-infection. The CC chemokines RANTES and MIP-1β were elevated in the broncho-alveolar lavage from animals treated intranasally with CpG-B compared to untreated and intraperitoneally dosed controls, and it is possible that these chemokines play a role in the clearance of intranasally delivered vaccinia virus.

Keywords: CpG-DNA; Orthopoxvirus; Innate immunity

Inhibition of herpesvirus replication by a series of 4-oxo-dihydroquinolines with viral polymerase activity by Caroll B. Hartline; Emma A. Harden; Stephanie L. Williams-Aziz; Nicole L. Kushner; Roger J. Brideau; Earl R. Kern (pp. 97-105).

Herpesviruses cause a wide variety of human diseases ranging from cold sores and genital herpes to encephalitis, congenital infections and lymphoproliferative diseases. These opportunistic viruses cause major problems in immunocompromised individuals such as transplant recipients, cancer patients, and HIV-infected persons. The current treatment of these infections is not optimal and there is a need for more active, less toxic compounds that might be used in place of or in addition to current therapies. We have evaluated a new series of 4-oxo-dihydroquinolines, which have a different mechanism of action than nucleosides and have activity against multiple herpesviruses. Of the four new compounds evaluated, two (PHA-529311 and PHA-570886) had greater activity than the parent, PHA-183792, against several herpesviruses and one (PHA-568561) was as effective as the parent. A fourth, PHA-243672, was considerably less effective. They had greater efficacy against cytomegalovirus (CMV) than the other herpesviruses tested and also had activity against acyclovir-resistant herpes simplex virus and varicella-zoster virus isolates and ganciclovir or foscarnet-resistant CMV isolates. These results confirm the broad-spectrum efficacy of these compounds against multiple herpesviruses and suggest that members of this class may have a potential role for treatment of a variety of herpesvirus infections.

Keywords: Herpesvirus; Antiviral; 4-Oxo-dihydroquinolines; Non-nucleosides; Polymerase

A novel HIV-1 antiviral high throughput screening approach for the discovery of HIV-1 inhibitors by Wade S. Blair; Jason Isaacson; Xinqiang Li; Joan Cao; Qinghai Peng; George F.Z. Kong; Amy K. Patick (pp. 107-116).

Antiviral high throughput screens remain a viable option for identifying novel target inhibitors. However, few antiviral screens have been reduced to practice on an industrial scale. In this study, we describe an HIV-1 dual reporter assay that allows for the simultaneous evaluation of the potential antiviral activities and cytotoxicities of compounds in a high throughput screen (HTS) format. We validate the assay with known HIV-1 inhibitors and show that the antiviral and cytotoxic activities of compounds are reproducibly measured under screening conditions. In addition, we show that the assay exhibits parameters (e.g., signal-to-background ratios and Z′ coefficients) suitable for high throughout screening. In a pilot screen, we demonstrate that non-specific or cytotoxic compounds represent a significant fraction of the hits identified in an antiviral screen and that these false positives are identified and deprioritized by the HIV-1 dual reporter assay at the primary screening step. We propose that the HIV-1 dual reporter assay represents a novel approach to HIV-1 antiviral screening that allows for the effective execution of industrial scale HTS campaigns with significantly greater returns on resource investment when compared to previous methods.

Keywords: HIV; Antiviral screen; Reporter virus; Cell-based assay

6-[1-(4-Fluorophenyl)methyl-1 H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester a novel diketo acid derivative which selectively inhibits the HIV-1 viral replication in cell culture and the ribonuclease H activity in vitro by Enzo Tramontano; Francesca Esposito; Roberta Badas; Roberto Di Santo; Roberta Costi; Paolo La Colla (pp. 117-124).

The human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT) is a multifunctional enzyme which displays DNA polymerase activity, which recognizes RNA and DNA templates, and a degradative ribonuclease H (RNase H) activity. While both RT functions are required for retroviral replication, until now only the polymerase function has been widely explored as drug target. We have identified a novel diketo acid derivative, 6-[1-(4-fluorophenyl)methyl-1 H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester (RDS 1643), which inhibits in enzyme assays the HIV-1 RT-associated polymerase-independent RNase H activity but has no effect on the HIV-1 RT-associated RNA-dependent DNA polymerase (RDDP) activity and on the RNase H activities displayed by the Avian Myeloblastosis Virus and E. coli. Time-dependence studies revealed that the compound is active independently on the order of its addition to the reaction mixture, and inhibition kinetics studies demonstrated that RDS 1643 inhibits the RNase H activity noncompetitively, with a K_I value of 17μM. When RDS 1643 was combined with non-nucleoside RT inhibitors (NNRTI), such as efavirenz and nevirapine, results indicated that RDS 1643 does not affect the NNRTIs anti-RDDP activity and that, vice versa, the NNRTIs do not alter the RNase H inhibition by RDS 1643. When assayed on the viral replication in cell-based assays, RDS 1643 inhibited the HIV-1_IIIB strain with an EC₅₀ of 14μM. Similar results were obtained against the Y181C and Y181C/K103N HIV-1 NNRTI resistant mutant strains. RDS 1643 may be the first HIV-1 inhibitor selectively targeted to the viral RT-associated RNase-H function.

Keywords: HIV; AIDS; Reverse transcriptase; Ribonuclease H; Antiviral agents; Diketoacid

YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action by Kenji Sudo; Yoji Miyazaki; Naoko Kojima; Masayuki Kobayashi; Hiroshi Suzuki; Masafumi Shintani; Yasuaki Shimizu (pp. 125-131).

We performed a large-scale random screening of an in-house chemical library based on the inhibition of respiratory syncytial virus (RSV)-induced cytopathic effect on HeLa (human cervical carcinoma) cells, and found a novel and specific anti-RSV agent, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}- N-cyclopropyl-5,6-dihydro-4 H-thieno[3,2- d][1]benzazepine-2-carboxamide (YM-53403). YM-53403 potently inhibited the replication of RSV strains belonging to both A and B subgroups, but not influenza A virus, measles virus, or herpes simplex virus type 1. A plaque reduction assay was used to determine the 50% effective concentration (EC₅₀) value for YM-53403. The value, 0.20μM, was about 100-fold more potent than ribavirin. The result of a time-dependent drug addition test showed that YM-53403 inhibited the life cycle of RSV at around 8h post-infection, suggesting an inhibitory effect on early transcription and/or replication of the RSV genome. Consistent with this result, two YM-53403-resistant viruses have a single point mutation (Y1631H) in the L protein which is a RNA polymerase for both the transcription and replication of the RSV genome. YM-53403 is an attractive compound for the treatment of RSV infection because of its highly potent anti-RSV activity and the new mode of action, which differs from that of currently reported antiviral agents.

Keywords: Respiratory syncytial virus; YM-53403; Ribavirin; L protein

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Antiviral Research (v.65, #2)

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Antiviral Research (v.65, #2)