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Danielson, U. Helena, ProfessorORCID iD iconorcid.org/0000-0003-2728-0340
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Publications (10 of 159) Show all publications
Linkuviene, V., Talibov, V. O., Danielson, U. H. & Matulis, D. (2018). Introduction of Intrinsic Kinetics of Protein-Ligand Interactions and Their Implications for Drug Design. Journal of Medicinal Chemistry, 61(6), 2292-2302
Open this publication in new window or tab >>Introduction of Intrinsic Kinetics of Protein-Ligand Interactions and Their Implications for Drug Design
2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 6, p. 2292-2302Article in journal (Refereed) Published
Abstract [en]

Structure kinetic relationship analyses and identification of dominating interactions for optimization of lead compounds should ideally be based on intrinsic rate constants instead of the more easily accessible observed kinetic constants, which also account for binding linked reactions. The intrinsic rate constants for sulfonamide inhibitors and pharmacologically relevant isoforms of carbonic anhydrase were determined by a novel surface plasmon resonance (SPR) biosensor-based approach, using chemodynamic analysis of binding-linked pH-dependent effects. The observed association rates (k(a)(obs)) were pH-dependent and correlated with the fraction of deprotonated inhibitor and protonated zinc-bound water molecule. The intrinsic association rate constants (k(a)(intr)) were pH independent and higher than k(a)(obs). By contrast, the observed and intrinsic dissociation rate constants were identical and pH-independent, demonstrating that the observed association and dissociation mechanisms are inherently different. A model accounting for the differences between intrinsic and observed rate constants was developed, useful also for other interactions with binding-linked protonation reactions.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-354359 (URN)10.1021/acs.jmedchem.7b01408 (DOI)000428356600008 ()29466001 (PubMedID)
Funder
Swedish Research Council, D0571301Carl Tryggers foundation
Available from: 2018-06-26 Created: 2018-06-26 Last updated: 2018-10-16Bibliographically approved
Pandya, N. J., Seeger, C., Babai, N., Gonzalez-Lozano, M. A., Mack, V., Lodder, J. C., . . . Smit, A. B. (2018). Noelin1 Affects Lateral Mobility of Synaptic AMPA Receptors.. Cell reports, 24(5), 1218-1230
Open this publication in new window or tab >>Noelin1 Affects Lateral Mobility of Synaptic AMPA Receptors.
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2018 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 24, no 5, p. 1218-1230Article in journal (Refereed) Published
Abstract [en]

Lateral diffusion on the neuronal plasma membrane of the AMPA-type glutamate receptor (AMPAR) serves an important role in synaptic plasticity. We investigated the role of the secreted glycoprotein Noelin1 (Olfactomedin-1 or Pancortin) in AMPAR lateral mobility and its dependence on the extracellular matrix (ECM). We found that Noelin1 interacts with the AMPAR with high affinity, however, without affecting rise- and decay time and desensitization properties. Noelin1 co-localizes with synaptic and extra-synaptic AMPARs and is expressed at synapses in an activity-dependent manner. Single-particle tracking shows that Noelin1 reduces lateral mobility of both synaptic and extra-synaptic GluA1-containing receptors and affects short-term plasticity. While the ECM does not constrain the synaptic pool of AMPARs and acts only extrasynaptically, Noelin1 contributes to synaptic potentiation by limiting AMPAR mobility at synaptic sites. This is the first evidence for the role of a secreted AMPAR-interacting protein on mobility of GluA1-containing receptors and synaptic plasticity.

Keywords
AMPAR-associated protein, glutamate receptor, receptor mobility, synapse function, synaptic plasticity
National Category
Biological Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-361395 (URN)10.1016/j.celrep.2018.06.102 (DOI)000440377500012 ()30067977 (PubMedID)
Funder
Swedish Research Council, D0571301
Available from: 2018-09-24 Created: 2018-09-24 Last updated: 2018-09-25Bibliographically approved
Belfrage, A. K., Abdurakhmanov, E., Åkerblom, E., Brandt, P., Alogheli, H., Neyts, J., . . . Johansson, A. (2018). Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold. European Journal of Medicinal Chemistry, 148, 453-464
Open this publication in new window or tab >>Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, p. 453-464Article in journal (Refereed) Published
Abstract [en]

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Hepatitis C, NS3, Genotype 3, Resistance, Pyrazinone
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-340862 (URN)10.1016/j.ejmech.2018.02.032 (DOI)000428824700036 ()
Funder
Swedish Research Council, D0571301
Available from: 2018-02-04 Created: 2018-02-04 Last updated: 2018-05-31Bibliographically approved
Seeger, C., Talibov, V. O. & Danielson, U. H. (2017). Biophysical analysis of the dynamics of calmodulin interactions with neurogranin and Ca2+/calmodulin-dependent kinase II. Journal of Molecular Recognition, 30, 1-11, Article ID e2621.
Open this publication in new window or tab >>Biophysical analysis of the dynamics of calmodulin interactions with neurogranin and Ca2+/calmodulin-dependent kinase II
2017 (English)In: Journal of Molecular Recognition, ISSN 0952-3499, E-ISSN 1099-1352, Vol. 30, p. 1-11, article id e2621Article in journal (Refereed) Published
Abstract [en]

Calmodulin (CaM) functions depend on interactions with CaM-binding proteins, regulated by Ca2+. Induced structural changes influence the affinity, kinetics, and specificities of the interactions. The dynamics of CaM interactions with neurogranin (Ng) and the CaM-binding region of Ca2+/calmodulin-dependent kinase II (CaMKII290-309) have been studied using biophysical methods. These proteins have opposite Ca2+ dependencies for CaM binding. Surface plasmon resonance biosensor analysis confirmed that Ca2+ and CaM interact very rapidly, and with moderate affinity (KDSPR=3M). Calmodulin-CaMKII290-309 interactions were only detected in the presence of Ca2+, exhibiting fast kinetics and nanomolar affinity (KDSPR7.1nM). The CaM-Ng interaction had higher affinity under Ca2+-depleted (KDSPR480nM,3.4x105M-1s-1 and k(-1) = 1.6 x 10(-1)s(-1)) than Ca2+-saturated conditions (KDSPR19M). The IQ motif of Ng (Ng(27-50)) had similar affinity for CaM as Ng under Ca2+-saturated conditions (KDSPR=14M), but no interaction was seen under Ca2+-depleted conditions. Microscale thermophoresis using fluorescently labeled CaM confirmed the surface plasmon resonance results qualitatively, but estimated lower affinities for the Ng (KDMST890nM) and CaMKII290-309(KDMST190nM) interactions. Although CaMKII290-309 showed expected interaction characteristics, they may be different for full-length CaMKII. The data for full-length Ng, but not Ng(27-50), agree with the current model on Ng regulation of Ca2+/CaM signaling.

Keywords
calmodulin, calmodulin-dependent kinase, surface plasmon resonance, microscale thermophoresis, neurogranin
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-329023 (URN)10.1002/jmr.2621 (DOI)000405095400006 ()
Funder
Swedish Research Council, D0571301
Available from: 2017-09-06 Created: 2017-09-06 Last updated: 2018-10-16Bibliographically approved
Abdurakhmanov, E., Solbak, S. O. & Danielson, U. H. (2017). Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase. Viruses, 9(6), Article ID 151.
Open this publication in new window or tab >>Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase
2017 (English)In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 9, no 6, article id 151Article in journal (Refereed) Published
Abstract [en]

Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.

Keywords
hepatitis C virus (HCV), non-structural protein (NS) polymerase, genotypes, allosteric inhibitor, surface plasmon resonance (SPR)
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-331940 (URN)10.3390/v9060151 (DOI)000405832000026 ()
Funder
Swedish Research Council, D0571301
Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2017-11-29Bibliographically approved
Solbak, S. M. .., Abdurakhmanov, E., Vedeler, A. & Danielson, U. H. (2017). Characterization of interactions between hepatitis C virus NS5B polymerase, annexin A2 and RNA - effects on NS5B catalysis and allosteric inhibition. Virology Journal, 14, Article ID 236.
Open this publication in new window or tab >>Characterization of interactions between hepatitis C virus NS5B polymerase, annexin A2 and RNA - effects on NS5B catalysis and allosteric inhibition
2017 (English)In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 14, article id 236Article in journal (Refereed) Published
Abstract [en]

Background: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy.

Methods: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition.

Results: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences.

Conclusions: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors.

Keywords
Hepatitis C virus, NS5B, Annexin A2, RNA, allosteric inhibition, filibuvir, surface, plasmon resonance, Hepatocellular carcinoma
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-337575 (URN)10.1186/s12985-017-0904-4 (DOI)000417867100001 ()29228983 (PubMedID)
Funder
Swedish Research Council, D0571301Carl Tryggers foundation
Available from: 2018-01-02 Created: 2018-01-02 Last updated: 2018-03-02Bibliographically approved
Nosrati, M., Solbak, S., Nordesjö, O., Nissbeck, M., Dourado, D. F. A., Andersson, K. G., . . . Flores, S. C. (2017). Insights from engineering the Affibody-Fc interaction with a computational-experimental method. Protein Engineering Design & Selection, 30(9), 593-601
Open this publication in new window or tab >>Insights from engineering the Affibody-Fc interaction with a computational-experimental method
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2017 (English)In: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 30, no 9, p. 593-601Article in journal (Refereed) Published
Abstract [en]

The interaction between the Staphylococcal Protein A (SpA) domain B (the basis of the Affibody) molecule and the Fc of IgG is key to the use of Affibodies in affinity chromatography and in potential therapies against certain inflammatory diseases. Despite its importance and four-decade history, to our knowledge this interaction has never been affinity matured. We elucidate reasons why single-substitutions in the SpA which improve affinity to Fc may be very rare, and also discover substitutions which potentially serve several engineering purposes. We used a variation of FoldX to predict changes in protein-protein-binding affinity, and produce a list of 41 single-amino acid substitutions on the SpA molecule, of which four are near wild type (wt) and five are at most a factor of four from wt affinity. The nine substitutions include one which removes lysine, and several others which change charge. Subtle modulations in affinity may be useful for modifying column elution conditions. The method is applicable to other protein-protein systems, providing molecular insights with lower workload than existing experimental techniques.

Keywords
Staphylococcal Protein A, affinity, computational prediction, protein-protein interactions, surface plasmon resonance
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-337576 (URN)10.1093/protein/gzx023 (DOI)000413767000004 ()28472513 (PubMedID)
Funder
Swedish Research Council, D0571301
Available from: 2018-01-02 Created: 2018-01-02 Last updated: 2018-02-16Bibliographically approved
Linkuviene, V., Talibov, V. O., Danielson, U. H. & Matulis, D. (2017). Intrinsic vs. observed thermodynamic and kinetic parameters of carbonic anhydrase-ligand interaction. Paper presented at 19th IUPAB Congress / 11th EBSA Congress, JUL 16-20, 2017, British Biophys Soc, Edinburgh, SCOTLAND. European Biophysics Journal, 46, S91-S91
Open this publication in new window or tab >>Intrinsic vs. observed thermodynamic and kinetic parameters of carbonic anhydrase-ligand interaction
2017 (English)In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 46, p. S91-S91Article in journal, Meeting abstract (Other academic) Published
National Category
Biophysics Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-347731 (URN)10.1007/s00249-017-1222-x (DOI)000416406200143 ()
Conference
19th IUPAB Congress / 11th EBSA Congress, JUL 16-20, 2017, British Biophys Soc, Edinburgh, SCOTLAND
Note

Supplement: 1, Meeting Abstract: P-749 (O-1

Also in: Volume: 46 (2017), Pages: S311-S311, Supplement: 1, Meeting Abstract: P-749 (O-1. ISI: 000416406201634

Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved
Fabini, E. & Danielson, U. H. (2017). Monitoring drug-serum protein interactions for early ADME prediction through Surface Plasmon Resonance technology. Journal of Pharmaceutical and Biomedical Analysis, 144, 188-194
Open this publication in new window or tab >>Monitoring drug-serum protein interactions for early ADME prediction through Surface Plasmon Resonance technology
2017 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 144, p. 188-194Article in journal (Refereed) Published
Abstract [en]

Many molecules fail to reach the market due to poor pharmacokinetic (PK) properties, rendering the potential drug virtually unavailable for the primary target despite efficient administration to the body. PK properties of endogenous and exogenous compounds in mammals are dependent, among other factors, on their ability to interact with serum proteins. The extent of binding can greatly influence their ADME (adsorption, distribution, metabolism and execration) profile. Reliable and cost-effective bioavailability studies, early in the drug discovery process, can lead to an improvement of the success rate for compounds entering clinical trials. Optical biosensors based on surface plasmon resonance (SPR) detection emerged as an efficient approach to obtain large amounts of information about the binding of small molecules to serum proteins. Simple, automated and fast assays provide a good throughput, versatility and highly informative data output, rendering the methodology particularly suited for early screening. The ability to provide basic information on PK can be easily coupled to structure-activity relationship analysis. In this review, features of the technology and its employment for the study of serum protein-small molecule interactions are presented and discussed. 

Keywords
Optical biosensor, Surface plasmon resonance spectroscopy, Early ADME profiling, Drug-serum proteins interaction, Human serum albumin, Alpha-1-acid glycoprotein
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-334396 (URN)10.1016/j.jpba.2017.03.054 (DOI)000408396400022 ()28392047 (PubMedID)
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-08Bibliographically approved
Belfrage, A. K., Abdurakhmanov, E., Åkerblom, E., Brandt, P., Oshalim, A., Gising, J., . . . Sandström, A. (2016). Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease. Bioorganic & Medicinal Chemistry, 24(12), 2603-2620
Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
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2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed) Published
Abstract [en]

Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

Keywords
Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
National Category
Organic Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
Funder
Swedish Research Council, D0571301
Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2728-0340

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