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.
1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues, were synthesized for evaluation as selective and potent nonnucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. The anti-HIV-1 activity of these compounds was assayed in vitro using HIV-1 infected MT-4 and CEM bioassays. The EC50, CC50 and SI were recorded and calculated. The appropriate position, especially in the 1-position of the naphthyl ring, led to dramatic increases in potency, in both MT-4 and CEM cellular assays. The most important compounds in this series, 1-ethoxymethyl-5-isopropyl-6-(1-naphthylmethyl)thymine 8l (IC50=17 nM, CC50=38332 nM, SI=2229) and 1-benzyloxymethyl-5-ethyl-6-(1-naphthylmethyl)thymine 8n (IC50=17 nM, CC50=32560 nM, SI=1889) were significantly more potent than HEPT (EC50=7.0 microM, CD50=740 microM) in the anti-HIV-1 in vitro cellular assay.
(E)-5-(2-Bromovinyl)-2'-deoxyuridine is a potent antiherpes compound with far better activity against herpes simplex virus type 1 than type 2. To understand the role of drug metabolism in this differential antiviral activity, we examined the metabolic fate of this drug in virus-infected and mock-infected Vero cells by high-pressure liquid chromatography. After 8 h of incubation in which cells were exposed to 10 micrograms of the drug per ml, 63 pmol/10(6) cells of the parent compound was detected in acid-soluble extracts of mock-infected cells. Herpes simplex virus-infected cells, however, incorporated or metabolized, or both, up to 11,310 pmol/10(6) cells. Type 1-infected cells metabolized the drug to the triphosphate where as many as 5,565 pmol/10(6) cells were detected. In contrast, three strains of type 2-infected cells metabolized the drug to the monophosphorylated nucleotide and no further. The amount of drug getting into the cells was virus strain and inoculum dependent. These studies indicate that poor substrate acceptance of (E)-5-(2-bromovinyl)-2'-deoxyuridine monophosphate by herpes simplex virus type 2-specified thymidylate kinase is an important factor in situ in infected cells, preventing anabolism of the parent compound to its active triphosphorylated form. This may account for its type specificity.
Combining multiple sensors on CMMs (Coordinate Measuring Machines) is useful to fulfil the increasing requirements on both complexity and accuracy in dimensional metrology. Yet, the methodology to plan measurement strategies for systems combining different types of sensors is still a major challenge. Such planning is commonly done in an interactive way. This paper presents a methodology which can create inspection plans automatically for CMM inspection combining a touch trigger probe and a laser scanner. The inspection features are specified based on the extracted geometry features and the associated PMI (Product and Manufacturing Information) items from a CAD model. A knowledge based sensor selection method is applied to choose the suited sensor for each inspection feature. For touch trigger measurements, the sampling strategy considers the measurement uncertainty calculated by simulation. A geometry-guide method is developed for collision-free probing path generation. For laser scan measurements, the required view angles and positions of the laser scanner are determined iteratively, based on which the scan path is generated automatically. The proposed methodology is tested for several cases and validated by measurement experiments. The methodology provides suited planning results and can be used for automated dimensional inspection, i.e. Computer Aided Quality Control (CAQC).
Several newly synthesized compounds, all structurally related to the highly potent and selective antiherpes agent bromovinyldeoxyuridine ( [E]-5-[2-bromovinyl]-2'-deoxyuridine), have been evaluated for their healing effect on herpes simplex virus type 1 keratitis in rabbits. These novel compounds included chloroethyldeoxyuridine (5-[2-chloroethyl]-2'-deoxyuridine), trifluoropropenyldeoxyuridine ( [E]-5-[3,3,3-trifluoro-1-propenyl]-2'-deoxyuridine), bromovinylaminodideoxyuridine ( [E]-5-[2-bromovinyl]-3'-amino-2',3'-dideoxyuridine), bromovinylarabinofuranosyluracil ( [E]-5-[2-bromovinyl]-1-beta-D-arabinofuranosyluracil), and glycylbromovinyldeoxyuridine (5'-O-aminoacetyl-[E]-5-[2-bromovinyl]-2'-deoxyuridine). Bromovinylaminodideoxyuridine and trifluoropropenyldeoxyuridine did not promote a significant healing of herpes simplex keratitis. Bromovinylarabinofuranosyluracil markedly reduced the severity of keratitis, but to a significantly lesser extent than bromovinyldeoxyuridine. Finally, chloroethyldeoxyuridine and glycylbromovinyldeoxyuridine caused a pronounced healing effect on herpes simplex keratitis, comparable to that obtained with bromovinyldeoxyuridine. Chloroethyldeoxyuridine was even slightly better than bromovinyldeoxyuridine, but the difference in their healing effect was not statistically significant.
No abstract is provided for this article.
Previous articleNext article FreeNew Biological BooksAntiviral Research: Strategies in Antiviral Drug Discovery. Edited by Robert L. LaFemina. Washington (DC): ASM Press. $169.95. xiii + 373 p. + 29 pl.; ill.; index. ISBN: 978-1-55581-439-7. 2009.Erik De ClercqErik De ClercqRega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium Search for more articles by this author Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, BelgiumPDFPDF PLUSFull Text Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinked InRedditEmailQR Code SectionsMoreThis book contains 20 articles that must have been written in (or before) 2008. Its content is rather comprehensive. It covers antiviral drug approaches toward a number of important human viral pathogens including HIV (human immunodeficiency virus), HSV (herpes simplex virus), HCV (hepatitis C virus), SARS (severe acute respiratory syndrome), coronavirus, influenza virus, pox- and flaviviruses, with a few additional chapters on microbicides, phenotypic susceptibility assays for HIV, metabolism of antiviral nucleosides and nucleotides, interferon response, toll-like receptors, and new HSV replication targets. HIV and HCV are particularly well covered, but several other viruses such as polyoma-, papilloma-, adeno-, picorna-, and hemorrhagic fever (other than the flavi-) viruses are hardly touched upon. And so are the herpesviruses other than HSV—i.e., varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesviruses type 6, 7, and 8 (VZV and CMV inhibitors are mentioned in Chapter 1 on antiherpesviral DNA polymerase inhibitors). The clinical aspects of HCV infection and treatment are well covered, but a similar chapter on hepatitis B virus (HBV), yet more prevalent than HCV, is lacking. HIV inhibitors targeted at either viral entry, reverse transcriptase, integrase, or protease are well described, but a synoptic view on the combination therapy with HIV inhibitors in clinical practice is not provided.From an aesthetic viewpoint, it is regrettable that the nice Chapter 10, Antiviral Targets in Orthopoxviruses, is interrupted (at least in the copy that I received) between pages 178 and 179 by 29 color plates, which should have better fitted in the chapters to which they belong or at the end of the book. All of the chapters have been carefully edited, are extensively referenced, and provide a comprehensive account on the topics they are discussing. The book concludes with an afterword with comments for further directions (although these comments have been apparently written independently from the regular chapters). Such an epilogue sets a laudable example for future volumes of this kind.In conclusion, the book offers a comprehensive snapshot on important antiviral drug strategies followed in the last decade for most, but not all, important viral pathogens, including HIV, HCV, HSV, influenza, SARS, pox- and flaviviruses. It should be of particular interest to those (experienced) readers who want to acquire recent information on the current state of the art in the antiviral drug research field. Previous articleNext article DetailsFiguresReferencesCited by The Quarterly Review of Biology Volume 86, Number 1March 2011 Published in association with Stony Brook University Article DOIhttps://doi.org/10.1086/658448 Views: 360Total views on this site Copyright © 2011 by The University of Chicago Press. All rights reserved.PDF download Crossref reports no articles citing this article.
