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Drug-resistant herpes simplex virus type 2 (HSV-2) strains were obtained under the selective pressure of acyclovir, ganciclovir, brivudin, foscamet, 2-phosphonyl-methoxyethyl (PME) derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), and 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of adenine (HPMPA) and cytosine (HPMPC; cidofovir). A significant degree of cross-resistance between HPMPC and HPMPA on the one hand, and between PMEA, PMEDAP and foscarnet on the other, was noted, suggesting a different mode of interaction of the PME and HPMP derivatives at the DNA polymerase level. The results described here with HSV-2 agree with the published results for HSV-1 and human cytomegalovirus.
Coupling of terminal alkynes with 5-iodo-1-(2,3,5-tri-O-p-toluyl-beta-D-arabinofuranosyl)uracil and 5-iodo-3',5'-di-O-p-toluyl-2'-deoxyuridine proceeded readily in triethylamine with catalytic quantities of bis(triphenylphosphine)-palladium(II) chloride and copper(I) iodide. The resulting products were deprotected to give 5-alkynyl-1-beta-D-arabinofuranosyluracil and 5-alkynyl-2'-deoxyuridine nucleosides. The 5-ethynyl, followed by 5-propynyl, products had the highest antiviral potency, with the 2'-deoxy derivatives being more effective than the arabinosyl compounds. Activity was weak at hexynyl and disappeared at heptynyl. Inclusion of an omega-hydroxy function diminished the antiviral effect. None of the 5-alkynyluracil nucleosides tested had sufficient selectivity to qualify as a candidate antiviral drug. Several of the compounds exerted an inhibitory action on thymidylate synthetase, with 5-ethynyl-2'-deoxyuridine being the most cytotoxic against L1210 cells.
Abstract 9-(2-Phosphonylmethoxyethyl)adenine (PMEA), the prototype compound of a well-defined structural class of potent and selective anti-retroviral agents, was found to be endowed with long-lasting and dose-dependent differentiation-inducing properties in human erythroleukemia K562 cell cultures.
The acyclic nucleoside phosphonates [HPMPC (cidofovir), PMEA (adefovir) and PMPA] have proved to the effective in vitro (cell culture systems) and in vivo (animal models, clinical studies) against a wide variety of DNA virus and retrovirus infections: i.e., HPMPC against herpesvirus (herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus types 6, 7, and 18), polyoma-, papilloma-, adeno-, and poxvirus (vaccinia virus, molluscum contagiosum virus) infections; PMEA against herpesvirus, hepadnavirus (human hepatitis B virus) and retrovirus (human immunodeficiency virus type 1 and 2, simian immunodeficiency virus, and feline immunodeficiency virus) infections; and PMPA against both hepadna- and retrovirus infections.
Topical administration of 0.1% or 1% chloroethyldeoxyuridine eyedrops caused a significant reduction in the severity of experimental herpes simplex iritis and stromal keratitis in rabbits. The healing effect caused by chloroethyldeoxyuridine was comparable to that obtained with 0.1% and 0.5% bromovinylde-oxyuridine eyedrops. The drug levels achieved in the anterior chamber fluid following topical application of 1% eyedrops of [2-14C]CEDU, a radiolabelled analogue of chloroethyldeoxyuridine, were well above the minimum concentration (0.1 microgram/mL) required for inhibition of herpes simplex virus type 1 replication. The beneficial effects of chloroethyldeoxyuridine on stomal keratitis and iritis appear consistent with its efficient penetration through the cornea.
The HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.
SummaryAthymic nude mice appear to be an ideal animal model to demonstrate the local Shwartzman reaction; in these mice the reaction can be provoked by both endotoxin and double-stranded RNA.This investigation was supported by grants from the F. G. W. O. (Fonds voor Geneeskundig Wetenschap-pelijk Onderzoek, krediet nr. 3.0048.75) and the Geconcerteerde Onderzoeksacties (Conventie nr. 76/81-IV). The authors are indebted to Dr. M. J. Van Stapel, Dr. C. Peeters and Prof. Dr. V. Desmet for histopathological examination of the skin biopsy specimens.
(S)-9-(2,3-Dihydroxypropyl)adenine, a novel nucleoside analog, the sugar moiety of which is replaced by an aliphatic chain, inhibits the replication in vitro of several DNA and RNA viruses, including vaccinia, herpes simplex (types 1 and 2), measles, and vesicular stomatitis. It is also effective in vivo in reducing the mortality rate of mice inoculated intranasally with vesicular stomatitis virus.
A series of novel 11-Indeno[1,2-b]quinoxalin-11-one have been synthesized by condensation of Indeno[1,2-b]quinoxalin-11-one and primary amines. Their chemical structures were assigned by means of spectral analysis (FT-IR, 1H-NMR). Synthesized compounds were screened for in vitro antiviral activity against HIV -1 and -2 in MT-4 cells and Cytotoxicity was also investigated in mock-infected MT-4 cells by using MTT assay. All the compounds exhibits cytotoxicity in MT-4 cellsand compound IDME-2ABT exhibited a distinct antiviral activity against HIV-2 (IC50: 2.55±0.23 µg/ml and CC50: 11.16±2.90 µg/ml, SI=4) in MT-4 cells.
