Dept. of Biochemistry & Organic Chemistry

Enzymology and drug discovery

Basic and applied research on important drug targets and critical aspects of drug discovery!

Our research group develops efficient and informative methods for analysis of enzymes. It is of relevance for basic research in the life sciences and for drug discovery. Activity-based assays and interaction assays using SPR-biosensor technology are combined for detailed studies of the characteristics of enzymes, their normal physiological function and regulation, and their inhibition by compounds that can be used in the discovery of novel drugs. The research is performed in collaboration with a biotech company (Biacore AB, Uppsala, Sweden), drug industry (Medivir AB, Huddinge, Sweden), a EU network of excellence (VIRGIL) and several academic research groups in Sweden and abroad. The research is of relevance for anti-viral research (HIV, HCV and CMV), anti-fungal research (Candidosis) and a variety of human diseases resulting from aberrant matrix metalloproteinase activity (COPD, cancer, arthritis etc). The research is primarily financed by Swedish governmental agencies (Vinnova, SIDA), EU (FP6) and other international governmental agencies (NIH/Population council).

Enzymes as drug targets

Enzymes of current interest:

HIV-1 protease
HIV-1 reverse transcriptase
Human CMV protease
HCV NS3 protease
HCV NS5B polymerase
Secreted proteases from Candida albicans
Matrix metalloproteinases (MMPs)

Biomolecular interaction analysis

Types of studies:

Screening of compound libraries
Mechanistic analysis of molecular interactions
Specificity/selectivity and resistance
Structure-kinetic relationships
Chemodynamics
Thermodynamics

HCV enzymology

The pathogenesis of HCV is complex and many aspects of the disease are being studied:

HCV NS3 protease inhibitor mechanisms and structure-activity relationships
HCV NS3 protease inhibitor resistance
HCV NS3 helicase interactions with protease substrate and inhibitors
HCV NS5B inhibition and interaction with RNA

Microbicides for prevention of spread of viral infections

NNRTIs for anti-HIV microbicides, resistance considerations

Nanobiotechnology

Development of nanoporous alumina for biotechnological applications

publications

2008

Hepatitis C virus NS3 protease inhibitors comprising a novel aromatic P1 moiety.

Rönn, R., Lampa, A., Peterson, S.D., Gossas, T., Åkerblom, E., Danielson, U.H., Karlén, A. and Sandström, A.

Bioorg Med Chem.; 2008; 16(6); 2955-67. DOI: 10.1016/j.bmc.2007.12.041

Identification of MMP-12 Inhibitors by Using Biosensor-Based Screening of a Fragment Library.

Nordström, H.; Gossas, T.; Hämäläinen, M.; Källblad, P.; Nyström, S.; Wallberg, H.; Danielson, U. H.

J. Med. Chem.; 2008; 51(12); 3449-3459. DOI: 10.1021/jm8000289

ß-Amino acid substitutions and structure-based CoMFA modelling of hepatitis C virus NS3 protease inhibitors.

Nurbo, J., Peterson, S.D., Dahl, G., Danielson, U.H., Karlén, A. and Sandström, A.

Bioorg Med Chem.; 2008; 16; 5590-5605. DOI: 10.1016/j.bmc.2008.04.005

2007

Mechanistic studies of electrophilic protease inhibitors of full length HCV NS3.

Poliakov, A., Sandström, A., Åkerblom, E. and Danielson, U.H.

J. Enzyme Inhibition and Medicinal Chemistry.; 2007; 22; 191-9.

Phenylglycine as a Novel P2 Scaffold in Hepatitis C Virus NS3 Protease Inhibitors.

Örtqvist, P., Peterson, S.D., Åkerblom, E., Gossas, T., Sabnis, Y.A., Fransson, R., Lindeberg, G., Danielson, U.H., Karlén, A. and Sandström, A.

Bioorganic & Medicinal Chemistry; 2007; 15:1448-1474.

Biomolecular Recognition of Glycosylated β3-Peptides by GalNAc Specific Lectins.

Norgren, A.S., Geitmann, M., Danielson, U.H, Arvidsson, P.I.

J. Molecular Recognition; 2007; 20; 132-138.

Evaluation of a diverse set of potential P1 carboxylic acid bioisosteres in hepatitis C virus NS3 protease inhibitors.

Robert Rönn, Thomas Gossas, Yogesh A. Sabnis, Hanna Daoud, Eva Åkerblom, U. Helena Danielson and Anja Johansson.

Bioorganic & Medicinal Chemistry; 2007; 15; 4057-4068.

Resistance profiling of HCV protease inhibitors using full-length NS3.

Dahl, G., Sandström, A., Åkerblom, E. and Danielson, U.H.

Antiviral Therapy; 2007; 12; 733-40.

Additional level of information about complex interaction between non-nucleoside inhibitor and HIV-1 reverse transcriptase using biosensor-based thermodynamic analysis.

Geitmann, M. and Danielson, U.H.

Bioorg Med Chem.; 2007; 15; 7344-54.

Effects on protease inhibition by modifying of helicase residues in hepatitis C virus non-structural protein 3.

Dahl, G., Sandström, A., Åkerblom, E. and Danielson, U.H.

The FEBS Journal, 2007; 274; 5979-5986. DOI: 10.1111/j.1742-4658.2007.06120.x

2006

Interaction kinetic characterization of HIV-1 reverse transcriptase non-nucleoside inhibitor resistance.

Geitmann M, Unge T, Danielson UH.
J Med Chem. 2006 Apr 20;49(8):2375-87.

Kinetic characterization of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors.

Geitmann, M., Unge, T. and Danielson, U.H.

J. Med. Chem., 2006, 49(8): 2367 - 2374.

Sensitivity analysis and error structure of progress curves.

Gutierrez, O.A. and Danielson, U.H.

Analytical Biochemistry, 2006, 358(1): 1-10.

Detection of enzyme inhibition with end point progress curve data. Gutierrez, O.A. and Danielson, U.H.

Analytical Biochemistry, 2006, 358(1): 11-19.

Characterization of Ca2+ Interactions with Matrix Metallopeptidase-12: Implications for Matrix Metallopeptidase regulation.

Gossas, T. and Danielson, U.H.

Biochemical Journal 2006, 398: 393-398.

Biosensor-based screening and characterization of HIV-1 inhibitor interactions with Sap 1, Sap 2, and Sap 3 from Candida albicans.

Backman D, Monod M, Danielson UH.
J Biomol Screen. 2006 Mar;11(2):165-75.

Exploration of acyl sulfonamides as carboxylic acid replacements in protease inhibitors of the hepatitis C virus full-length NS3.

Robert Rönn, Yogesh A. Sabnis, Thomas Gossas, Eva Åkerblom, U. Helena Danielson, Anders Hallberg and Anja Johansson.

Bioorganic & Medicinal Chemistry, 2006,14(2):544-59.

Inhibition of viral proteases by Zingiberaceae extracts, a new source for antiviral lead compounds: HIV-1 Protease inhibitors from Kaempferia parviflora.

Sookkongwaree, K., Geitmann, M., Roengsumran, S., Petsom, A. and Danielson, U.H.

Pharmazie, 2006, 61(8):717-721.

Recent posters (2008)

COLLABORATORS & FUNDING AGENCIES





Carl Tryggers Stiftelse för Vetenskaplig Forskning