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- Andersson, H.O., et al.
(författare)
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Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
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- Dahlgren, Anders, et al.
(författare)
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New inhibitors of the malaria aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:16, s. 3423-3437
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Tidskriftsartikel (refereegranskat)abstract
- New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits Ki values of 250 nM and 1.4 µM for Plm I and II, respectively. © 2003 Elsevier Ltd. All rights reserved.
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| 9. |
- Dahlgren, Anders, et al.
(författare)
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Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:6, s. 827-841
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Tidskriftsartikel (refereegranskat)abstract
- With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 µM (Ki for Plm II=5.4 µM). © 2003 Elsevier Science Ltd. All rights reserved.
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- 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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