Antiviral Chemotherapy Research Articles

Antiviral Briefs

AIDS Patient Care and STDsVol. 20, No. 12 Antiviral BriefsPublished Online:27 Dec 2006https://doi.org/10.1089/apc.2006.20.887AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byNovel Compounds for the Treatment of HIV Type-1 Infection1 April 2009 | Antiviral Chemistry and Chemotherapy, Vol. 19, No. 5 Volume 20Issue 12Dec 2006 InformationCopyright 2006, Mary Ann Liebert, Inc.To cite this article:Antiviral Briefs.AIDS Patient Care and STDs.Dec 2006.887-889.http://doi.org/10.1089/apc.2006.20.887Published in Volume: 20 Issue 12: December 27, 2006PDF download

Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design

BackgroundDevelopment of countermeasures to bioterrorist threats such as those posed by the smallpox virus (variola), include vaccination and drug development. Selective activation of nucleoside analogues by virus-encoded thymidine (dThd) kinases (TK) represents one of the most successful strategies for antiviral chemotherapy as demonstrated for anti-herpes drugs. Vaccinia virus TK is a close orthologue of variola TK but also shares a relatively high sequence identity to human type 2 TK (hTK), thus achieving drug selectivity relative to the host enzyme is challenging.ResultsIn order to identify any differences compared to hTK that may be exploitable in drug design, we have determined the crystal structure of VVTK, in complex with thymidine 5'-triphosphate (dTTP). Although most of the active site residues are conserved between hTK and VVTK, we observe a difference in conformation of residues Asp-43 and Arg-45. The equivalent residues in hTK hydrogen bond to dTTP, whereas in subunit D of VVTK, Asp-43 and Arg-45 adopt a different conformation preventing interaction with this nucleotide. Asp-43 and Arg-45 are present in a flexible loop, which is disordered in subunits A, B and C. The observed difference in conformation and flexibility may also explain the ability of VVTK to phosphorylate (South)-methanocarbathymine whereas, in contrast, no substrate activity with hTK is reported for this compound.ConclusionThe difference in conformation for Asp-43 and Arg-45 could thus be used in drug design to generate VVTK/Variola TK-selective nucleoside analogue substrates and/or inhibitors that have lower affinity for hTK.

Tumor Lysis Syndrome Associated With Reduced Immunosuppression in a Lung Transplant Recipient

Tumor lysis syndrome usually occurs after Initiation of chemotherapy or radiation therapy in cancer patients with a moderate to high tumor burden. To our knowledge, the occurrence of this syndrome after discontinuation or reduction of an immunosuppressive regimen has not been reported in the literature. We describe a patient who had undergone lung transplantation and who was receiving immunosuppression and experienced an episode of acute pancreatitis. During the course of the work-up, the patient was found to have a B-cell lymphoma (posttransplantation lymphoproliferative disease). His tacrolimus dosage was decreased, and azathioprine was discontinued. The patient subsequently developed tumor lysis syndrome. Other than the decrease in immunosuppression, we found no other factor that could have accounted for this syndrome.

Silencing of HIV-1 genes using siRNA-expressing genetic constructs

Today antiviral chemotherapy is the main methodto control HIV infection. Common medications influ-ence primarily the key enzymes of HIV-1, such asreverse transcriptase, integrase, and protease. How-ever, in spite of a large quantity of existing anti-HIVdrugs, antiviral therapy is often ineffective. The mainreason for ineffectiveness of treatment is adaptivemutagenesis of the virus, causing the appearance ofnew HIV-1 variants resistant to antiviral drugs. Thetoxicity and high cost of such drugs also present aserious problem.It is known that RNA interference is a powerfulnatural mechanism involved in the regulation of geneexpression and protection of cells against foreignRNA; it is also called ancient immunity operating atthe RNA level [1]. Recently, it has been found thatRNA interference is regulated during the developmentof an organism [2]. Viruses have the capacity to regu-late RNA interference. In the course of evolution, theyacquired the ability to turn off RNA interference in thehost cell to ensure their own reproduction [3]. Severalyears ago, we proposed artificial RNA interference forboth the investigation of its mechanisms and the use ofsilencing of HIV-1 genes in gene therapy. Now severalresearch groups are working in this field [4–6]. In thispaper, we report the results of testing three geneticconstructs for suppression of HIV-1 production inhuman cells.We induced artificial RNA interference using shorthairpin genetic constructs. Such constructs containshort palindromic sequences separated by a shortloop. The palindromic regions of RNA moleculesform hairpins. Owing to the existing cell mechanismof RNA monitoring, such double-stranded RNAs(dsRNAs) are detected and processed by Dicer(RNase III) to yield double-stranded small interferingRNA (siRNA). At the second stage of RNA interfer-ence, only the antisense siRNA strand remains withinthe RNA-induced silencing complex (RISC). A nucle-otide sequence of the siRNA within RISC is used tosearch for complementary regions in cell RNAs. In thecase of an HIV-1-specific siRNA, RISC recognizes anavailable single-stranded region in viral transcriptsand cuts it.The efficiency of siRNA is determined by a num-ber of factors. In particular, it depends on the siRNAnucleotide composition, which should meet the fol-lowing empiric requirements [7, 8]: a GC content of30–52%, at least three A/U in positions 15–19 of thesense strand, lack of internal repeats, A in positions 19and 3 of the sense strand, U in position 10 of the sensestrand, lack of G/C in position 19 of the sense strand,lack of G in position 13 of the sense strand, etc. Theavailability of target RNA is the second factor deter-mining the efficiency of siRNA. If the mRNA regioncomplementary to siRNA is unavailable (for example,it is bound to a protein or included in a duplex), thenit cannot be degraded.We began our study when these requirements wereunknown, so we proceeded from the assumptions thatthe best targets in HIV-1 transcripts are the most con-served regions within the functionally importantdomains and that biologically active siRNAs can beisolated in direct tests for suppression of virus produc-tion.We searched for HIV-1 conserved regions with theuse of the BLAST program and multiple sequencealignment. Within the AF316544 sequence of HIV-1subtype A, we found the most conserved regions cor-responding to the protease, reverse transcriptase, andTat domains. These regions were chosen as targets forsiRNA-encoding constructs. The resulting siRNAs

Interferon‐γ as an Antifungal

I (D.A.S.) am honored to be able to make this contribution. Although other presenters have dwelled on Tom Merigan's many contributions to both AIDS studies and antiviral chemotherapy generally, I can emphasize another role for him, that of helping to bring interferon (IFN) to the fore of our consciousness [1]. I have the pleasant, unique role of being the only contributor not now identified with virology, and I will address the discipline to which I transitioned after fellowship with Tom-a place where, it turns out, IFN has an important host role [2]. Charles Prober, of the Department of Pediatrics at Stanford, recently made me aware that I have been, with my colleagues, publishing on IFN in 5 different decades now.

Multiple sclerosis is linked to Epstein‐Barr virus infection

The aetiology and pathogenesis of MS are unknown, but environmental agents, genetic susceptibility and stochastic events are likely to be involved. In order to evaluate the possibility that MS is linked to EBV infection, we here evaluate studies on MS- and EBV-epidemiology, prospective and retrospective analysis of EBV-serology, investigations of EBV DNA sequences in blood and tissues, specificity of antibodies in oligoclonal bands in MS patients and results from antiviral chemotherapy of MS patients. It could be demonstrated that EBV is complying with the epidemiological observations in MS and that all MS patients are seropositive to EBV in contrast to healthy controls. Importantly, despite difficulties in diagnosing child-MS, the vast majority of these patients are also EBV seropositive. In contrast to control groups, recent EBV infections have never been observed in children or adults with MS. Further prospective studies indicate a 2.8 times higher tendency for development of MS after infectious mononucleosis. In MS patients, unbiased analyses pull out EBV antigens as high-affinity targets for the antibodies in the oligoclonal bands. Humans are the exclusive natural host for EBV, a finding that may explain why MS is unique to humans. Together these unique observations strongly suggest a linkage between MS and EBV infection. Infection by EBV offers numerable mechanisms to perturb the immune system, including mimicry and superantigen induction, which may potentially participate in the disease mechanisms. In contrast, studies demonstrating higher IgG titres and occurrence of viral DNA in serum/plasma are likely to reflect a consequence of the disease. An explanation for a potential role of respiratory diseases in MS is discussed. It is concluded that the ultimate test to the hypothesis of MS and EBV is the development and application of an EBV vaccine, which is predicted to eradicate the disease.

Antivirals for influenza: Historical perspectives and lessons learned

The development of the currently available classes of antivirals, the M2 proton channel inhibitors and the neuraminidase inhibitors, provides valuable perspectives relevant to the field of antiviral chemotherapy in general and insights into aspects of viral pathogenesis and antiviral resistance relevant specifically to influenza. The efficacy observed with these antiviral drugs has proven the importance of these antiviral targets, as well as the principle that chemoprophylaxis and early treatment are possible in influenza infections with small molecular weight inhibitors.

Antiviral Chemistry & Chemotherapy's Current Antiviral Agents FactFile 2006 (1st Edition) the DNA Viruses

<i>Antiviral Chemistry &amp; Chemotherapy</i>'s Current Antiviral Agents FactFile 2006 (1st Edition) the DNA Viruses

Safe adoptive transfer of virus‐specific T‐cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation

During periods of immunosuppression, such as postallogeneic stem cell transplantation (SCT), patients are at significant risk for severe viral infections. Human adenovirus (HAdV) infection is a serious complication post-SCT, especially in children. Virus-specific T cells are essential for the clearance of HAdV, as antiviral chemotherapy has revealed limited success. We present feasibility data for a new treatment option using virus-specific donor T cells for adoptive transfer of immunity to patients with HAdV-infection/reactivation. Virus-specific donor T cells were isolated and infused into nine children with systemic HAdV infection after SCT. Isolation was based on gamma-interferon (IFN-gamma) secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4(+) and CD8(+) T cells. 1.2-50 x 10(3)/kg T cells were infused for adoptive transfer. Isolated cells showed high specificity and markedly reduced alloreactivity in vitro. Adoptive transfer of HAdV-specific immunity was successful in five of six evaluable patients, documented by a dose-independent and sustained in vivo expansion of HAdV-specific T cells, associated with a durable clearance/decrease of viral copies. T-cell infusion was well tolerated in all nine patients, except one case with graft-versus-host disease II of the skin. In conclusion, induction of a specific T-cell response through adoptive transfer was feasible and effective. When performed early in the course of infection, adoptive T-cell transfer may protect from HAdV-related complications.

L-Nucleoside enantiomers as antivirals drugs: A mini-review

The discovery that some nucleoside analogues endowed with the unnatural l-configuration can possess biological activities has been a significant breakthrough in antiviral chemotherapy. In this regard, lamivudine (3TC) was the first l-nucleoside enantiomer approved against HIV and HBV, and several other l-nucleosides are currently under clinical development as antiviral agents

Studies of interaction between a new synthesized minor-groove targeting artificial nuclease and DNA

Nuclease plays an important role in molecular biology, such as DNA sequencing. Synthetic polyamide conjugates can be considered as new tool in the selective inhibition of gene expression and as potential drugs in anticancer or antiviral chemotherapy. In this paper, a new synthesized minor-groove targeting artificial nuclease, oligopyrrol-containing peptide, was reported. It was found that this new compound can bind DNA in AT-riched minor groove with high affinity and site specificity. DNA binding behavior was determined by UV–vis and circular dichroism (CD) methods. It was indicated that compound 6 can enhance the T m of oligomer DNA from 51.8 to 63.5 °C and possesses large binding constant ( K b = 8.83 × 10 4 L/mol).

LB film of hybrid polyoxometalate: Sm-POM encapsulated with dodecyltrimethylammonium cation

Polyoxometalates (POMs) have high potential applications in various fields such as magnetic nanoparticles, energy transfer, luminescence, catalysts and antiviral chemotherapy. The polyoxometalates with long alkyl groups were synthesized. Sodium cations of SmW 10O 36 9− were exchanged the counter ions by dodecyltrimethyl ammonium cations (DDTA) to obtain a hybrid Sm-containing polyoxometalate in which hydrophilic polyoxometalate cores are encapsulated by hydrophobic shells. The Langmuir-Blodgett film was fabricated from the hybrid POM. The hybrid POM layer spread onto water surface exhibited stability against surface pressure up to 50 mN/m. The IR, UV and XPS spectra indicated the presence of hybrid POM structure. The surface images of the hybrid POM LB films were observed by AFM.

Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules

Pronucleotides represent a promising tool to improve the biological activity of nucleoside analogs in antiviral and cancer chemotherapy. The cycloSal-approach is one of several conceptually different pronucleotide systems. This approach can be applied to various nucleoside analogs. A salicyl alcohol as a cyclic bifunctional masking unit is used, and shown to afford a chemically driven release of the particular nucleotide from the lipophilic phosphate triester precursor molecule. A conceptual extension of the cycloSal-approach results in the design of “lock-in”- cycloSal-derivatives. The cycloSal-approach is not restricted to the delivery of bioactive nucleotides but also useful for the intracellular delivery of hexose-1-phosphates.

CycloSal Phosphates as Chemical Trojan Horses for Intracellular Nucleotide and Glycosylmonophosphate Delivery — Chemistry Meets Biology

AbstractPronucleotides represent a promising alternative to improve the biological activity of nucleoside analogs in antiviral and cancer chemotherapy. In addition, pronucleotides are valuable tools for studies regarding the nucleoside/nucleotide metabolism. The aim is to achieve nucleotide delivery into cells and thereby bypass limitations during intracellular formation of nucleotides from their nucleoside precursors. The cycloSal approach is one of several conceptually different pronucleotide systems known but is the only approach in which a pronucleotide is cleaved successfully by simple but selective chemical hydrolysis. The basic concept, chemistry, different structural modifications, and their effects on the antiviral potency of the cycloSal d4TMP triesters are briefly discussed first. Then, the application of the approach to various biologically active nucleoside analogs against different targets is summarized. In the second part, the results of a conceptual extension of the cycloSal approach are presented: once cycloSal pronucleotides have passed the membrane, they should be trapped inside the cells after an enzyme‐catalyzed process and then release the nucleotide. Finally, results are summarized that demonstrate that the cycloSal approach is not restricted to the delivery of bioactive nucleotides but is also applicable to the intracellular delivery of hexose‐1‐phosphates. Chemical synthesis, biophysical studies, and biological evaluation will be discussed in combination throughout this paper to demonstrate the strength of the cycloSal approach. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2006)

Identification of in Vivo Phosphorylation Sites on Human Deoxycytidine Kinase: ROLE OF SER-74 IN THE CONTROL OF ENZYME ACTIVITY

Deoxycytidine kinase (dCK) catalyzes the rate-limiting step of the deoxyribonucleoside salvage pathway in mammalian cells and plays a key role in the activation of numerous nucleoside analogues used in anti-cancer and antiviral chemotherapy. Although compelling evidence indicated that dCK activity might be regulated by phosphorylation/dephosphorylation, direct demonstration was lacking. Here we showed that dCK overexpressed in HEK 293T cells was labeled after incubating the cells with [32P]orthophosphate. Sorbitol, which was reported to decrease dCK activity, also decreased the labeling of dCK. These results indicated that dCK may exist as a phosphoprotein in vivo and that its activity can be correlated with its phosphorylation level. After purification of 32P-labeled dCK, digestion by trypsin, and analysis of the radioactive peptides by tandem mass spectrometry, the following four in vivo phosphorylation sites were identified: Thr-3, Ser-11, Ser-15, and Ser-74, the latter being the major phosphorylation site. Site-directed mutagenesis and use of an anti-phospho-Ser-74 antibody demonstrated that Ser-74 phosphorylation was crucial for dCK activity in HEK 293T cells, whereas phosphorylation of other identified sites did not seem essential. Phosphorylation of Ser-74 was also detected on endogenous dCK in leukemic cells, in which the Ser-74 phosphorylation state was increased by agents that enhanced dCK activity. Our study provided direct evidence that dCK activity can be controlled by phosphorylation in intact cells and highlights the importance of Ser-74 for dCK activity.

Antiviral prodrugs – the development of successful prodrug strategies for antiviral chemotherapy

Following the discovery of the first effective antiviral compound (idoxuridine) in 1959, nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirus infections, have dominated antiviral therapy for several decades. However, ACV and similar acyclic nucleosides suffer from low aqueous solubility and low bioavailability following oral administration. Derivatives of acyclic nucleosides, typically esters, were developed to overcome this problem and valaciclovir, the valine ester of ACV, was among the first of a new series of compounds that were readily metabolized upon oral administration to produce the antiviral nucleoside in vivo, thus increasing the bioavailility by several fold. Concurrently, famciclovir was developed as an oral formulation of penciclovir. These antiviral 'prodrugs' thus established a principle that has led to many successful drugs including both nucleoside and nucleotide analogues for the control of several virus infections, notably those caused by herpes-, retro- and hepatitisviruses. This review will chart the origins and development of the most important of the antiviral prodrugs to date.

Adoptive Transfer of Adenovirus Specific T-Cells in Children with Systemic Adenovirus Infection after Allogeneic Stem Cell Transplantation.

Allogeneic stem cell transplantation (SCT) has become an increasing treatment option for a variety of malignant and non-malignant disease. During immune reconstitution the host is at significant risk for viral infections. Human adenovirus (HAdV) infection is especially in children an important and serious complication. Virus-specific T-cells are essential for the clearance of HAdV, since antiviral chemotherapy has been insufficient to date. We present a new treatment option using virus-specific donor T-cells for adoptive transfer of immunity to patients with systemic HAdV-infection. We isolated in 6 patients with systemic HAdV-infection after SCT virus-specific T-cells of the donor, according to INF-γ secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T-cells. Between 5-50x103/kg T-cells were infused for adoptive transfer. For follow-up, the infection and the in-vivo expansion of infused T-cells were evaluated. Isolated cells showed high specificity and markedly reduced but residual alloreactivity in-vitro. In three of four evaluable patients the infused T-cells underwent an in-vivo expansion and in these three patients the viral load decreased in peripheral blood after adoptive T-cell transfer. In-vivo expansion of specific T-cells was dose-independent. T-cell infusion was well tolerated. One patient experienced GvHD°II of the skin after T-cell transfer. In conclusion specific T-cell immunotherapy as a new treatment approach for children was performed in 6 cases of systemic HAdV-infection after allogeneic SCT. Induction of a specific T-cell response through adoptive transfer has been shown feasible and effective to protect from HAdV-related complications.

Dendritic Cell Vaccination Induces HCMV Specific T-Cell Responses in Allogeneic Stem Cell Recipients.

Human cytomegalovirus (HCMV) infection remains a major and life threatening infectious complication after allogeneic stem cells transplantation (SCT). We performed a Dendritic cell (DC) vaccination trial by utilizing HCMV peptide loaded mature DC to boost HCMV specific T-cell responses which have been demonstrated to be protective against the development of HCMV disease. DCs were pulsed with nonamer peptides from the HCMV proteins pp65 and pp150, restricted by the HLA-class I elements A1,A2,A3,A11,A68 and B7. We enrolled 24 allogeneic SCT recipients, 6 patients received prophylactic vaccination in view of high risk for HCMV disease. 18 patients were vaccinated therapeutically after HCMV reactivation failed to respond to 4 weeks course of antiviral chemotherapy. Our primary objectives were safety and feasibility of DC vaccination after allogeneic SCT. As all patients with active HCMV infections already received antiviral chemotherapy at the time of DC vaccination, viral load was not a suitable efficacy parameter. Thus, evaluation of efficacy as a secondary objective was based on reconstitution of HCMV-specific CTL responses and long term control of HCMV infection. The study protocol was approved by the local ethical committee and all patients gave written informed consent. DC were generated under GMP conditions and displayed typical surface markers of mature DC (CD1a+/CD14−/CD83+). No local or systemic acute side effects occurred during the first week post vaccination. An observation period of 3 months was determined to evaluate long term side effects and control of HCMV infection. Six patients died during this observation period from other causes and one had no follow-up blood samples, so, 17 patients (5 received prophylactic and 12 received therapeutic vaccination) were evaluable. Only one patient developed Graft-Versus-Host-Disease (GVHD) grade III of the skin and gut. Due to a time lag of 2 months between vaccination and the onset of GVHD, a causative relationship seems to be unlikely. Four of the five patients receiving prophylactic vaccination never showed HCMV reactivation. 10 patients from the therapeutic group cleared their HCMV infection after a mean of 50 days post vaccination. Therefore, 15 of the 17 evaluable patients demonstrated control of HCMV infection after DC vaccination. Among these 15 patients, 10 had detectable specific T-cell response against the vaccine peptides after a mean of 23 days post vaccination. Only 2 from these 10 patients developed a further HCMV reactivation after high dose steroid therapy. Our results show that no relevant side effect was observed in this first DC vaccination trial among allogeneic SCT patients. Additionally, DC are able to induce an efficient peptide specific immune response among allogeneic SCT patients which is capable to protect against HCMV reactivation. In the future, further investigations should be performed to evaluate the feasibility of DC vaccination not only against other infectious complications but also against tumour associated antigens to induce specific T-cell response effectively targeting the particular tumour cell.

In Vitro Expansion of CMV-Specific T Cells from CMV Seronegative Donors.

CMV infection is still a negative prognostic factor in hematopoietic stem cell transplantation, largely due to adverse effects of antiviral chemotherapy. Advances have been made in the development of adoptive cellular therapy for CMV with cell products derived from CMV seropositive donors. However no such cell products from CMV negative donors are currently available, although CMV negative recipients of CMV positive grafts bear the greatest risk of CMV induced morbidity and mortality. Mature DC are capable of inducing in vivo primary T cell responses. We used an in vitro culture system employing MoDC generated with GM-CSF and IL-4, pulsed with CMV lysate and matured with CD40L to induce primary immune responses to CMV. CMV-specific T cell proliferation measured by 3H-Thymidine uptake could be induced in some 6 to 9-day cultures, however, the success rate was very low, and T cells could usually not be kept alive after becoming activated. The addition of IL-15 to cultures after 7 days resulted in some improvement, although some non-CMV specific T cell proliferation in response to control lysate or in the absence of antigen also occurred in some cultures. IL-12 added to cultures from day 0 resulted in a short-term increase in T cell proliferation that was followed by increased cell death and was also not entirely CMV-specific. The real benefit of IL-15, alone or in combination with IL-12, was seen in 2-week cultures: In 6/7 cultures from different CMV seronegative donors counts of viable T cells (by trypan blue exclusion) increased up to 10-fold. Two cultures that were additionally set up with control lysate-pulsed DC to detect proliferation in response to non-CMV components of the antigen, confirmed CMV-specificity.CMV-specificity was also shown by T cell receptor (TCR) complement determining region (CDR) 3 spectratyping. TCR-BV(variable region β)-size class expression patterns across 23 BV families were very similar in pre-culture unstimulated T cells and in T cells stimulated with control lysate-pulsed DC for 2 weeks, showing the typical near-normal distribution of PCR product amongst the different size classes indicative of un-stimulated T cells. T cells co-cultured with CMV lysate-pulsed DC for 2 weeks produced very skewed spectratypes, indicative of oligoclonal T cell expansion in response to the antigen. The effect of IL-15 on T cell spectratypes from CMV antigen-driven cultures was tested using cells from another donor. With or without IL-15, post-culture spectratypes showed oligoclonal T cell expansions in the same BV families and size classes. However, despite their similar shapes, spectratypes from IL-5 containing cultures were skewed to a greater extent, possibly indicating a greater effect of IL-15 on already activated T cells.No CD8+ T cells specific for single immunodominant epitopes could be detected by staining with up to 5 different HLA-CMVpeptide-tetramers in culture output from 4/4 donors. In 1 of 2 cultures analyzed by cytokine secretion assay, a significant sub-population of T cells (1%), in CD4 positive and negative fractions, secreted IFN-γ in response to re-stimulation with CMV antigen. No IFN-γ secreting CMV-specific pre-cursor T cells were detected in fresh PBMC, as expected. Whilst further work is required to make generation of CMV specific T cells from CMV seronegative donors more reproducible and to ensure antigen-specificity, these preliminary data are encouraging for the future generation of CMV-specific T cells from CMV seronegative donors for adoptive cellular therapy.

Synthesis of Novel Test Compounds for Antiviral Chemotherapy of Severe Acute Respiratory Syndrome (SARS)

This contribution reviews the synthesis of a range of experimental drugs designed for and aiming at antiviral chemotherapy of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV)-induced human disease conditions. The selection of 25 test materials includes eleven trioxa-adamantane-triols (TATs) [BN, IBNCA, ABNCA, VANBA, ethylVANBA, euBN, euVANBA, ansaBN, Ehrlich BN, [6]prismaneBN, nitrodiBN], trivially termed bananins, one trioxa-adamantan-ol (TAO) THYMOBA, one bis-bananin pi-bananin (piBN), one triazaadamantane delta-bananin (deltaBN), seven potential nucleic acid-binding drugs (XBQC, INDO, PivINDO, AZTRION, AZADO, AZOCYS, AZOGALL), one potential antiviral interferon-inducer and distant nucleoside analog diazon, one potential HIV protein Vif antagonist AZODIAZON, one folic acid-diazon condensate DIAZONOFOL, and one special nucleoside analog (fructoinosine/fructovir). Four of the eleven bananins (BN, IBNCA, VANBA, euBN) were already demonstrated to constitute effective inhibitors of SARS-CoV NSP10/nsp13 RNA/DNA helicase/NTPase protein ATPase enzymatic function. Bananin (BN) was an effective inhibitor of both SARS-CoV RNA/DNA helicase nucleic acid unwinding function and SARS-CoV (Coronaviridae, Coronavirus) RNA-viral replication in cell culture. In summary, at least one selected compound of the synthesized test materials represents an interesting drug candidate for treatment of SARS-CoV-induced human disease (SARS). Viewed in aspects of organic chemistry [6]prismaneBN and nitrodiBN are the first true hexaprismane derivatives synthesized, and all reported compounds are entirely new.