| 1. |
- Wu, Xiongyu, et al.
(author)
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Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
- 2008
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:4, s. 1053-1057
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Journal article (peer-reviewed)abstract
- A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.
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| 2. |
- Castell, Alina, 1977-
(author)
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Fighting Tuberculosis – : Structural Studies of Three Mycobacterial Proteins
- 2008
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Doctoral thesis (other academic/artistic)abstract
- This thesis presents the cloning, purification, crystallization, and structural studies of two unknown proteins from Mycobacterium tuberculosis, and of an aminotransferase from Mycobacterium smegmatis. Structural knowledge of these proteins is of highest interest for structure-based drug design, which is one of the approaches that can be used in order to fight tuberculosis (TB). The structure of the conserved hypothetical protein Rv0216 was refined to a resolution of 1.9 Å. The structure exhibits a so-called double hotdog-fold, similar to known hydratases. However, only parts of the hydratase active site are conserved in Rv0216, and no function could be assigned to the protein. Several Rv0216-like protein sequences were found in a variety of actino- and proteobacteria, suggesting that these proteins form a new protein family. Furthermore, other hotdog-folded proteins in M. tuberculosis were identified, of which a few are likely to be hydratases or dehydratases involved in the fatty acid metabolism. The structure of Rv0130 exhibits a single hotdog-fold and contains a highly conserved R-hydratase motif. Rv0130 was shown to hydrate fatty acid coenzyme A derivatives with a length of six to eight carbons. The Rv0130 active site is situated in a long tunnel, formed by a kink in the central hotdog-helix, which indicate that it can utilize long fatty acid chains as well. A number of previously predicted hotdog-folded proteins also feature a similar tunnel. The structure of branched chain aminotransferase (BCAT) of M. smegmatis was determined in the apo-form and in complex with an aminooxy inhibitor. Mycobacterial BCAT is very similar to the human BCAT, apart for one important difference in the active site. Gly243 is a threonine in the human BCAT, a difference that offers specificity in inhibition and substrate recognition of these proteins. The aminooxy compound and MES were found to inhibit the mycobacterial BCAT activities. The aminooxy compound inhibits by blocking the substrate-pocket. A second inhibitor-binding site was identified through the binding of a MES molecule. Therefore, both the MES-binding site and the substrate-pocket of M. smegmatis BCAT are suggested to be potential sites for the development of new inhibitors against tuberculosis.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Ekegren, Jenny K, et al.
(author)
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A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold
- 2005
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:25, s. 8098-8102
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Journal article (peer-reviewed)abstract
- Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1‘−P3‘ residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented.
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| 7. |
- Ekegren, Jenny K, et al.
(author)
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Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold
- 2006
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:5, s. 1828-1832
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Journal article (peer-reviewed)abstract
- Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.
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| 8. |
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| 9. |
- Elinder, Malin, et al.
(author)
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MIV-170 : A novel NNRTI exhibiting tight binding to HIV-1 reverse transcriptase (RT)
- 2008
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In: Antiviral Research. - : Elsevier BV. - 0166-3542.
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Conference paper (peer-reviewed)abstract
- The NNRTI MIV-170 has been found to be a very efficient inhibitor of wtHIV and HIV mutant strains resistant to the NNRTIs used in the clinic. To better understand the interaction between MIV-170 and HIV-1 the details of this have been studied by different methods. The kinetics of the interaction between MIV-170 and HIV-1 RT was analysed using a biosensor assay. The association and dissociation rates were determined using immobilized wtRT or RT mutants and MIV-170 as analyte. The results demonstrated that MIV-170 had both a faster association and a slower dissociation rate than efavirenz, nevirapine and delavirdine, thus exhibiting a higher affinity than these compounds. The strength of the interaction between the NNRTIs and RT and RT mutants in the biosensor assay was compared to the reversibility of inhibition in cell culture experiments. In these experiments virus and infected cells were incubated with MIV-170 and other NNRTIs for various times and after removal of the compounds the remaining infectivity was assayed. X-ray analysis of the binding of MIV-170 to HIV-1 RT displayed extensive interactions, not only between the compound and the lining amino acids but also between these residues, turning the binding cavity into a rigid entity and explaining the tight binding in the biosensor assay and the inactivation of HIV.
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