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Optimization of P1-...
Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
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- Andersson, H.O. (author)
- Uppsala universitet,Institutionen för naturvetenskaplig biokemi,Institutionen för cell- och molekylärbiologi,Biokemi, Mannervik,Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden,Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden
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- Fridborg, K. (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
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- Lowgren, S. (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Löwgren, S., Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
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- Alterman, M. (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi,Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden,Mühlman, A., Department of Organic Chemistry, Stockholm University, Stockholm, Sweden
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- Muhlman, A. (author)
- Mühlman, A., Department of Organic Chemistry, Stockholm University, Stockholm, Sweden
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- Bjorsne, M. (author)
- Björsne, M., Department of Organic Chemistry, Stockholm University, Stockholm, Sweden
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- Garg, N. (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi,Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden
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- Kvarnström, Ingemar (author)
- Linköpings universitet,Tekniska högskolan,Organisk Kemi
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- Schaal, Wesley (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi,Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden
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- Classon, B. (author)
- Department of Organic Chemistry, Stockholm University, Stockholm, Sweden
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- Karlen, A. (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi,Karlén, A., Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden
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- Danielson, U. Helena (author)
- Uppsala universitet,Institutionen för naturvetenskaplig biokemi,Department of Biochemistry, Uppsala University, Uppsala, Sweden
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- Ahlsen, G. (author)
- Uppsala universitet,Institutionen för naturvetenskaplig biokemi,Ahlsén, G., Department of Biochemistry, Uppsala University, Uppsala, Sweden
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- Nillroth, U. (author)
- Uppsala universitet,Institutionen för naturvetenskaplig biokemi,Department of Biochemistry, Uppsala University, Uppsala, Sweden
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- Vrang, L. (author)
- Medivir AB, Lunastigen 7, Huddinge, Sweden
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- Oberg, B. (author)
- Öberg, B., Medivir AB, Lunastigen 7, Huddinge, Sweden
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- Samuelsson, B. (author)
- Department of Organic Chemistry, Stockholm University, Stockholm, Sweden
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- Hallberg, A. (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Unge, T. (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden, Inst. of Cell and Molecular Biology, Box 590, Uppsala University, SE-751 24 Uppsala, Sweden
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(creator_code:org_t)
- Wiley, 2003
- 2003
- English.
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In: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
- Related links:
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https://febs.onlinel...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- AIDS
- Drug
- HIV
- Protease
- X-ray
- TECHNOLOGY
- TEKNIKVETENSKAP
- Biochemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Andersson, H.O.
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Fridborg, K.
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Lowgren, S.
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Alterman, M.
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Muhlman, A.
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Bjorsne, M.
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show more...
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Garg, N.
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Kvarnström, Inge ...
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Schaal, Wesley
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Classon, B.
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Karlen, A.
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Danielson, U. He ...
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Ahlsen, G.
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Nillroth, U.
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Vrang, L.
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Oberg, B.
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Samuelsson, B.
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Hallberg, A.
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Unge, T.
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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European Journal ...
- By the university
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Linköping University
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Uppsala University