| 1. |
- Ahlsén, Göran, et al.
(författare)
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Resistance profiles of cyclic and linear inhibitors of HIV-1 protease
- 2002
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Ingår i: Antiviral Chemistry & Chemotherapy. - 0956-3202 .- 2040-2066. ; 13:1, s. 27-37
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Tidskriftsartikel (refereegranskat)abstract
- Resistance to anti-HIV protease drugs is a major problem in the design of AIDS drugs with long-term efficacy. To identify structural features associated with a certain resistance profile, the inhibitory properties of a series of symmetric and asymmetric cyclic sulfamide, cyclic urea and linear transition-state analogue inhibitors of HIV-1 protease were investigated using wild-type and mutant enzyme. To allow a detailed structure-inhibition analysis, enzyme with single, double, triple and quadruple combinations of G48V, V82A, 184V and L90M substitutions was used. Kinetic analysis of the mutants revealed that catalytic efficiency was 1-30% of that for the wild-type enzyme, a consequence of reduced kcat in all cases and an increased KM for all mutants except for the G48V enzyme. The overall structure-inhibitory profiles of the cyclic compounds were similar, and the inhibition of the V82A, 184V and G48V/L90M mutants were less efficient than of the wild-type enzyme. The greatest increase in Ki was generally observed for the 184V mutant and least for the G48V/L90M mutant, and additional combinations of mutations did not result in improved inhibition profiles for the cyclic compounds. An extended analysis of additional mutants, and including a set of linear compounds, showed that the profile was unique for each compound, and did not reveal any general structural features associated with a certain inhibition profile. The effects of structural modifications in the inhibitors, or of mutations, were not additive and they differed depending on their context. The results demonstrate the difficulties in predicting resistance, even for closely related compounds, and designing compounds with improved resistance profiles.
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| 2. |
- BALZARINI, J, et al.
(författare)
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OXATHIIN CARBOXANILIDE DERIVATIVES - A CLASS OF NONNUCLEOSIDE HIV-1-SPECIFIC REVERSE-TRANSCRIPTASE INHIBITORS (NNRTIS) THAT ARE ACTIVE AGAINST MUTANT HIV-1 STRAINS RESISTANT TO OTHER NNRTIS
- 1995
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Ingår i: ANTIVIRAL CHEMISTRY & CHEMOTHERAPY. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 6:3, s. 169-178
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The HIV-1-specific oxathiin carboxanilide derivative 1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)carbonyl]amino]benzoate (NSC 615985) (designated UC84) has potent activity against HIV-1(IIIB) (50% effective concentration: 0.015 μg ml−1). UC84 was found to select for a 138-Lys mutant virus strain in HIV-1-infected CEM cell cultures. When the 138-Lys mutation was introduced solely in the p51 subunit of the p51/p66 reverse transcriptase (RT) heterodimer by site-directed mutagenesis, the enzyme proved 10-fold more resistant to UC84 than when the amino acid mutation was introduced solely in the p66 subunit of the p51/p66 RT heterodimer. These data provided clear evidence for a structural and functional role of the p51 subunit in the sensitivity/resistance of the enzyme to UC84. UC84 also proved to be virtually inactive against mutant HIV-1 strains containing the 100-lle, 106-Ala, 138-Lys or 181-Cys mutation in their RT. However, minor structural changes in the molecule, such as replacement of the oxygen of the amide moiety by sulfur, or the isopropyl ester moiety by cyclopentyl or a secondary butyl, or the methyl group of the oxathiin part by ethyl, made the compound markedly more inhibitory to one or several HIV-1 mutant strains. For example, compound 131 (1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)thioxomethyl]amino]benzoate was only 2-fold more active than the parent compound UC84 against wild-type HIV-1, but 30- to 100-fold more inhibitory to HIV-1 mutant strains that contained the 100-11e, 106-A1a, 138-Lys or 181-Cys in their RT. These findings should be taken into account when selecting suitable drug candidates for the treatment of HIV-1 infections, particularly those that have developed resistance to other non-nucleoside RT inhibitors (NNRTIs).
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| 3. |
- Borg, N, et al.
(författare)
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Distribution to the brain and protein binding of 3' and 5-substituted 2',3'-dideoxyuridine derivatives, studied by microdialysis
- 1997
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Ingår i: ANTIVIRAL CHEMISTRY & CHEMOTHERAPY. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 8:1, s. 47-53
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this study was to investigate a series of 3′ and 5-substituted 2′,3′-dideoxyuridine derivatives (ddUD) with respect to plasma protein binding, half-life and distribution across the blood-brain barrier in the rat. The microdialysis technique was used to study protein binding in human plasma ( in vitro), and to sample the extracellular space of rats with microdialysis probes implanted into the striatum of the brain and the gastrocnemic muscle ( in vivo). The compounds were analysed by HPLC with UV-detection. The octanol/water partition coefficients of the ddUD varied from 0.08-0.84. The protein binding of the ddUDs was approximately 80%. After s.c. administration (25 or 50 mg kg−1), the brain and muscle extracellular levels differed; brain levels were 0.18-0.36 of peripheral (muscle) concentrations. A multivariate analysis, which included data on zidovudine, alovudine and thymidine, demonstrated a relationship between the physicochemical and some of the pharmacokinetic properties of uridine analogues. The analysis shows that half-life and protein binding increases with decreasing p Ka. However, penetration to the brain is not correlated with the partition into octanol. It is concluded that the transport to the brain is not primarily dependent upon passive diffusion over a lipophilic barrier but, rather, to other chemical properties of the ddUDs. This is suggestive of a specific transport mechanism, e.g. the thymidine carrier.
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| 4. |
- Borg, N, et al.
(författare)
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Penciclovir pharmacokinetics and distribution to the brain and muscle of rats, studied by microdialysis
- 1997
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Ingår i: ANTIVIRAL CHEMISTRY & CHEMOTHERAPY. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 8:3, s. 275-279
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Famciclovir, the oral form of penciclovir, is a potent, highly selective antiherpesvirus agent licenced for the treatment of herpes zoster (shingles). Some herpesviruses are prone to infect the central nervous system. To obtain guidance for the possible treatment of herpes encephalitis it is important to study the extent of transport of antiviral agents into the brain. We have used microdialysis to sample the unbound extracellular concentration of penciclovir in the gastrocnemic muscle (which corresponds directly to plasma free concentrations) and in the brain of rats under halothane anaesthesia. Penciclovir (50 mg kg−1) was given intravenously (i.v.) and samples were taken for 5 h after administration. The AUC (area under the time versus concentration curve) (0–5 h) of penciclovir in the brain was 0.096±0.018 (mean±SEM) of the AUC in muscle while the mean ratio of brain to muscle concentration 5 h post-injection was 0.1 80±0.084. Famciclovir given per os to rat at a dose of 1 20 mg kg−1 resulted in a concentration ratio for penciclovir between brain and muscle of 0.415±0.078 at 5 h after administration, while the AUC ratio (0–5 h) was 0.143±0.012. Both of these are higher than after i.v. injection of penciclovir. Penciclovir and famciclovir were also administrated by i.v. infusion (60 and 80 mg kg−1 h−1 respectively). Famciclovir administration (AUC 0.075±0.025 mmol h L−1) did not increase penciclovir transport to the brain compared with penciclovir administration (AUC 0.163±0.018 mmol h L−1).
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| 5. |
- Harmenberg, JG, et al.
(författare)
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ME-609: a treatment for recurrent herpes simplex virus infections
- 2003
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Ingår i: Antiviral chemistry & chemotherapy. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 14:4, s. 205-15
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Tidskriftsartikel (refereegranskat)abstract
- Studies in conventional murine models of HSV infection use immunologically naive animals. These models thus mimic primary infections rather than recurrent infections in humans. We have, therefore, used a newly developed mouse model that more closely mimics recurrent HSV infection in humans. In this model, the mice are infected, and zosteriform HSV-1 infection develops in the presence of a primed immune response using adoptive transfer of immunity (ATI) as we have described previously. Using the ATI mouse model, it has been shown that a more beneficial therapy for recurrent mucocutaneous HSV infection could be achieved by controlling both the viral replication and the inflammatory response to the virus. Topical treatment was initiated in this model at the time of first occurrence of symptoms and was given three times daily for 4 days. Topical treatment with ME-609 (which contains 5% acyclovir and 1% hydrocortisone) in the ATI mouse model was substantially more efficacious than 5% Zovirax® cream, 1% hydrocortisone or no treatment, respectively. The beneficial properties of ME-609 were also found to be superior to those of Zovirax cream when tested in the standard guinea pig model, representing a primary HSV infection. ME-609 represents a novel treatment principle of recurrent HSV infections and the present paper summarizes the preclinical and early clinical experience of ME-609.
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| 6. |
- Maloisel, JL, et al.
(författare)
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Neoglycolipid conjugates of foscarnet with enhanced antiviral activity in cells infected with human cytomegalovirus and herpes simplex virus type 1
- 1999
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Ingår i: Antiviral chemistry & chemotherapy. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 10:6, s. 333-345
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis of a series of neoglycolipid conjugates of foscarnet as potential drug targeting forms or lipophilic prodrugs of foscarnet is described. The compounds were obtained from suitably protected neoglycolipids, in which the lipid chain consisted of 12 to 20 carbon atoms, by ethoxycarbonylphosphonylation at the 6-hydroxyl or 4-hydroxyl group followed by deprotection. The in vitro antiviral activity of the compounds was determined in human foetal lung cells infected with human cytomegalovirus (HCMV) or herpes simplex virus type 1 (HSV-1). Compounds in which the lipid chain consisted of 14 to 20 carbon atoms showed pronounced antiviral activity against HCMV and HSV-1, the highest activity being shown by trans-9-octadecen-1-yl 6- O-carboxyphosphonyl-α-D-glucopyranoside against HCMV (approximately 50 times that of foscarnet) and by eicosyl 6- O-carboxyphosphonyl-β-D-galactopyranoside against HSV-1 (approximately 15 times that of foscarnet). Cytotoxicity was determined by assessing the capability of mitochondrial enzymes to metabolise MTT and gave TC50 values for the compounds that were 30 to 350 times higher than their IC50 values against HCMV and 5 to 15 times higher than their IC50 values against HSV-1. Foscarnet was not liberated on incubation of n-tetradecyl 6- O-carboxyphosphonyl-á-D-glucopyranoside with rat liver or intestine homogenate, neither could the neoglycolipid conjugate nor foscarnet be detected in rat plasma following oral administration. Further metabolic and pharmacokinetic studies are required in order to determine whether neoglycolipid conjugates of foscarnet can find a use as drug targeting forms of foscarnet.
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| 7. |
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| 8. |
- Palmer, S, et al.
(författare)
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Intracellular metabolism of 3'-azido-3'-deoxythymidine in the presence of ganciclovir or foscarnet
- 1996
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Ingår i: ANTIVIRAL CHEMISTRY & CHEMOTHERAPY. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 7:1, s. 14-20
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Comparisons were made between the intracellular phosphorylation of 3′-Azido-3′-deoxythymidine (AZT) alone and in combination with ganciclovir (GCV) or foscarnet (PFA) in lymphocytes, uninfected fibroblasts and CMV-infected fibroblasts. The effects of AZT and the combinations of AZT with GCV or PFA on cellular dNTP pools were also examined. The phosphorylation of AZT was not altered by the presence of GCV or PFA in lymphocytes, and neither AZT nor the combinations of AZT with GCV or PFA changed the levels of cellular dNTP pools in these cells. AZT was phosphorylated to a greater extent in lymphocytes when compared to fibroblasts, but the proportion of AZT di- and triphosphates was greater in fibroblasts. The infection of fibroblasts with CMV enhanced AZT phosphorylation and increased the levels of cellular dNTP pools. GCV caused a specific reduction in AZT phosphorylation in CMV-infected fibroblasts, with a seven-fold drop in AZT triphosphate compared to AZT alone. GCV did not affect AZT phosphorylation in uninfected fibroblasts, nor did GCV reduce the dTTP pool compared to AZT alone. The effects of GCV upon AZT phosphorylation in CMV-infected cells may shed light on the antagonistic effects of GCV upon the anti-HIV activity of AZT, and are of importance for the development of effective combination therapies for the treatment of AIDS patients infected with CMV.
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| 9. |
- Zhang, H, et al.
(författare)
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Synergistic inhibition of HIV-1 reverse transcriptase and HIV-1 replication by combining trovirdine with AZT, ddl and ddC in vitro
- 1996
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Ingår i: ANTIVIRAL CHEMISTRY & CHEMOTHERAPY. - : SAGE Publications. - 0956-3202 .- 2040-2066. ; 7:5, s. 221-229
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Trovirdine (LY300046·HCI) is a potent and selective non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor (Åhgren et al., Antimicrob Ag Chemother 39: 1329, 1995). Combinations of trovirdine with other RT inhibitors, AZT, ddC., ddl and their triphosphates, were studied as well as the pyrophosphate analogue PFA in both cell-free HIV-1 polymerase assays and HIV-1-infected MT-4 cell cultures. Synergistic effects and weak synergism were observed both using RT and HIV-1 - infected cells and using different HIV-1 RT mutants and HIV-1 drug-resistant variants known to be resistant to the inhibitory effects of trovirdine. The best combination with substantial synergism was ddC-TP and trovirdine at a 20:1 molar ratio combination in a cell-free enzyme assay. This combination showed the weak synergy in MT-4 cells. Synergism was judged by the median-effect method. The inhibitory effect of trovirdine was independent of increased concentrations of AZT triphosphate and ddC triphosphate implying that trovirdine acts in a mutually exclusive manner with AZT-TP and ddC-TP as determined by the Dixon plot. The combination effects were expressed by the combination index (Cl) using end points of 50%, 70% and 90% inhibition of HIV-1 RT activity and HIV-1 replication in MT-4 cells.
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| 10. |
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