ASP2151 is a novel herpes helicase-primase inhibitor that warrants further investigation for the potential treatment of both VZV and HSV infections.
Twenty antiherpes compounds were compared for their inhibitory activities against five laboratory strains and five clinical isolates of varicella-zoster virus (VZV) in human embryo fibroblast cultures. E-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), E-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), and E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) were the most effective. The average values of the 50% inhibitory dose (ID50) for VZV replication were 0.0013, 0.0015, and 0.0024 micrograms/ml, respectively. 1-beta-D-Arabinofuranosyladenine and 9-(2-hydroxyethoxymethyl)guanine were 1.2 and 3.4 times less effective than 5-iodo-2'-deoxyuridine (IDU). The selectivity indexes (ratio of ID50 for host-cell DNA synthesis to ID50 for VZV replication) of BVaraU, IVDU, and BVDU were between 41,000 and 67,000, whereas those of cytosine arabinoside, IDU, and 5-bromo-2'-deoxyuridine were less than 1.1. BVaraU, IVDU, and BVDU were the most potent and the most selective inhibitors of VZV activity. A deoxythymidine kinase deficient mutant of VZV was resistant to most of the compounds tested at concentrations up to 36,000 times greater than the average ID50 for strains that were not deficient.
By using an assay system based on a human hepatoblastoma cell line (HB611) that continuously synthesizes hepatitis B virus DNA, the following compounds were found to inhibit hepatitis B virus DNA synthesis at concentrations that were significantly lower than their minimum cytotoxic concentrations: 9-(2-phosphonylmethoxyethyl)-2,6-dianiinopurine (PMEDAP), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, 9-(phosphonylmethoxyethyl)adenine, 2',3'-dideoxy-2',3'-didehydrocytidine, and 2',3'-dideoxycytidine. The most potent compound was PMEDAP (50% effective concentration, 0.02 pg/ml). The Recently, a number of assay systems have been described which seem suitable for evaluation of the inhibitory effects of antiviral compounds against hepadnaviruses, including HBV and duck hepatitis B virus (DHBV) (5, 9, 11, 13, 15). DHBV is able to propagate in primary duck hepatocytes in vitro (12). Selective inhibition of the synthesis of DHBV DNA and core antigen in primary duck hepatocytes can be used as a marker for anti-DHBV activity. Using this assay system, we examined a variety of purine and pyrimidine nucleoside analogs for their inhibitory effects on DHBV replication (15).Ueda et al. (13) have recently described a human hepatoblastoma cell line (HB611) that contains an integrated HBV genome and that accumulates a significant amount of HBV DNA replicative intermediates. Some of these DNA molecules are packed and released as Dane particles into the cell culture medium. Selective inhibition of the synthesis of these replicative intermediates could serve as a marker for anti-HBV activity. Using the HB611 cell line, we examined the inhibitory effects of selected antiviral compounds on HBV DNA synthesis. The compounds which we evaluated for their inhibitory effect on HBV DNA synthesis were previously examined for their inhibitory effects on DHBV DNA and core antigen synthesis in primary duck hepatocytes (15).The compounds fell into two categories: phosphonylmethoxyalkylpurines and -pyrimidines and 2',3'-dideoxynucleoside analogs. Their origins were as follows. Test compounds were assayed by a modification of the method described by Ueda et al. (13). The HB611 cell line was generously provided by K. Matsubara, Institute for Molecular and Cellular Biology, Osaka University, Osaka, Japan. HB611 cells were seeded in tissue culture trays (diameter, 35 mm) at a density of 5 x 104 cells per well by using Dulbecco modified minimum essential medium supplemented with 10% fetal bovine serum, 100 ,ug of streptomycin per ml, 100 IU of penicillin G per ml, and 0.2 mg of Geneticin R (GIBCO) per ml. After 2 days of incubation, when the cells were grown to confluency, the growth medium was withdrawn. Then, the cells were incubated for 12 days, during which time the medium containing the compounds was exchanged every 3 days. The cells were then harvested and total DNA was prepared upon lysis of the cells in 0.5 ml of 10 mM Tris hydrochloride (pH 7.8)-S5 mM EDTA-150 mM NaCI-1% sodium dodecyl sulfate-0.1 mg of proteinase K (Sigma) per ml. After...
Duck hepatitis B virus (DHBV) replication in primary duck hepatocytes was monitored by examining the synthesis of both DHBV DNA and DHBV core antigen. Several nucleoside analogs which were previously shown to inhibit the replication of DNA viruses (i.e., herpesviruses) and retroviruses were examined for their inhibitory effects on the synthesis of DHBV core antigen in primary duck hepatocytes. (S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine, 2',3'-dideoxyadenosine, and 2',3'-dideoxycytidine inhibited DHBV core antigen synthesis at concentrations that were significantly lower than those found to be toxic to the primary hepatocytes. Of all the compounds tested, (S)-HPMPA showed the lowest 50% effective concentration (0.5 ,ug/ml). The selectivity index or ratio of the 50% cytotoxic concentration to the 50% effective concentration of (S)-HPMPA was greater than 300. (S)-HPMPA not only inhibited DHBV core antigen but also DHBV DNA synthesis in DHBV-infected hepatocytes.Human hepatitis B virus (HBV) is a causative agent of both an acute and chronic form of hepatitis. More than 200 million people worldwide are estimated to be chronic carriers of HBV. HBV belongs to the family Hepadnaviridae, which also includes woodchuck hepatitis virus, ground squirrel hepatitis virus, tree squirrel hepatitis virus, and duck hepatitis B virus (DHBV) (3,(7)(8)(9)(10)(11)(12)(13)(14)19). All members of the hepadnavirus family have a number of characteristics in common such as morphological appearance, antigenic makeup, and DNA size and structure (3,(7)(8)(9)(10)(11)(12)(13)(14)19). Also, the pathological findings following infection with these viruses are quite similar (8,20). The replication of the hepadnaviruses (4, 10) is dependent on the reverse transcription of an RNA intermediate. This results in the formation of a minusstranded DNA, which then serves as a template for the synthesis of plus-stranded DNA.DHBV is able to propagate in primary duck hepatocytes in vitro. Tuttleman et al. (21) reported that upon infection of primary duck hepatocytes with DHBV, viral DNA is synthesized, virus-specific proteins are produced, and infectious virus is released into the culture medium. Using immunofluorescence, they demonstrated the production of both core and surface DHBV antigens in primary duck hepatocytes that were infected with DHBV. This in vitro system should prove suitable to evaluate the effects of antiviral drugs against DHBV. In this study, we examined a wide variety of such drugs that belong to the class of the purine and pyrimidine nucleoside analogs for their inhibitory effects on replication of DHBV in primary duck hepatocytes in vitro. was from ICN Nutritional Biochemicals, Cleveland, Ohio; 2',3'-dideoxy-2',3'-didehydrothymidine (D4T), 2',3'-dideoxyuridine (DDU), 2',3'-dideoxyadenosine (DDA), 2',3'-dideoxycytidine (DDC), 3'-deoxyarabinofuranosylcytidine (D-ara-C), 3'-azido-2',3'-dideoxythymidine (AZT), 3'-azido-2',3'-dideoxyuridine (AZU), acyclovir [9-(2-hydroxyeth...
A set of 20 nucleoside analogs were examined for their inhibitory effects on the cytopathogenicity and growth of influenza virus type A, B, and C strains in Madin-Darby canine kidney (MDCK) cells. Among the compounds evaluated, pyrazofurin, 3-deazaguanine, ribavirin, carbodine, and cyclopentenyl cytosine inhibited viral cytopathogenicity at concentrations that were lower than those found cytotoxic for the MDCK cells. No differences were observed in the 50% effective doses (based on inhibition of viral cytopathogenicity) of these five compounds for a number of influenza virus type A (subtypes HlNl and H3N2), B, and C strains. Pyrazofurin showed the lowest 50% effective dose (0.15 ,ug/ml), which was about 20-to 30-fold lower than those of the other four compounds. The selectivity indices of the five compounds, calculated as the ratio of the 50% cytotoxic dose (determined by trypan blue exclusion) to the 50% effective dose, were greater than 100. When the selectivity indices were calculated as the ratios of the 50% inhibitory doses for cellular RNA synthesis to the 50% effective doses, they were greater than 100 for ribavirin, pyrazofurin, and 3-deazaguanine but less than 2 for carbodine and cyclopentenyl cytosine. All five compounds inhibited the growth of influenza virus types A and B in MDCK cells at a concentration which was well below their cytotoxicity threshold for MDCK cells and, therefore, deserve further exploration for their potential in the treatment of influenza virus type A, B, and C infections.
Ingenol 3,5,20-triacetate (ITA), one of the ingenol derivatives, is a selective inhibitor of human immunodeficiency virus (HIV) replication in vitro. ITA inhibited the replication of HIV strains in MT-4 cells at concentrations of 0.051 to 0.65 microM. This concentration was approximately 10(3)-fold lower than its cytotoxic threshold. The mechanism of action of ITA is primarily attributed to the inhibition of viral adsorption to the host cells, but it is distinct from the mechanism of inhibition by other adsorption inhibitors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.