uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Andersson, Hanna, Dr.ORCID iD iconorcid.org/0000-0003-3798-3322
Publications (10 of 15) Show all publications
Karim, A., Schulz, N., Andersson, H., Nekoueishahraki, B., Carlsson, A.-C. C., Sarabi, D., . . . Erdélyi, M. (2018). Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally. Journal of the American Chemical Society, 140(50), 17571-17579
Open this publication in new window or tab >>Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally
Show others...
2018 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 50, p. 17571-17579Article in journal (Refereed) Published
Abstract [en]

Tetrel bonding is the noncovalent interaction of group IV elements with electron donors. It is a weak, directional interaction that resembles hydrogen and halogen bonding yet remains barely explored. Herein, we present an experimental investigation of the carbon-centered, three-center, four-electron tetrel bond, [N-C-N](+), formed by capturing a carbenium ion with a bidentate Lewis base. NMR-spectroscopic, titration-calorimetric, and reaction-kinetic evidence for the existence and structure of this species is reported. The studied interaction is by far the strongest tetrel bond reported so far and is discussed in comparison with the analogous halogen bond. The necessity of the involvement of a bidentate Lewis base in its formation is demonstrated by providing spectroscopic and crystallographic evidence that a monodentate Lewis base induces a reaction rather than stabilizing the tetrel bond complex. A vastly decreased Lewis basicity of the bidentate ligand or reduced Lewis acidity of the carbenium ion weakens or even prohibits the formation of the tetrel bond complex, whereas synthetic modifications facilitating attractive orbital overlaps promote it. As the geometry of the complex resembles the S(N)2 transition state, it provides a model system for the investigation of fundamental reaction mechanisms and chemical bonding theories.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-373369 (URN)10.1021/jacs.8b09367 (DOI)000454383400038 ()30484646 (PubMedID)
Funder
Swedish Research Council, ME 2016:03602
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Palica, K., Andersson, H. & Erdélyi, M. (2018). Development of Metallo-β-lactamase Inhibitors to Control Antibiotic Resistance. In: EMBO Course: Multidimensional NMR in Structural Biology Joachimsthal 2018: . Paper presented at EMBO Course: Multidimensional NMR in Structural Biology, Joachimsthal, 12-19 Aug 2018..
Open this publication in new window or tab >>Development of Metallo-β-lactamase Inhibitors to Control Antibiotic Resistance
2018 (English)In: EMBO Course: Multidimensional NMR in Structural Biology Joachimsthal 2018, 2018Conference paper, Poster (with or without abstract) (Refereed)
Abstract [en]

The aim of this project is focused on existing antibiotics, their transition states – EI and creation of new bioisosteres, which can have both inhibition and antibiotics properties.This strategy allows for the avoidance of combinatorial therapy and use medicine with widespectrum of action. 

In this project, subclasses of MβLs (between them: NMD-12) will be tested with series of β-lactam antibiotics transition state, which first will be synthesise. NMR studies are essentialfor success of this project. Evaluation of the complexes of MβLs and the transition stateanalogues will be studied by solution NMR to provide information of their activity. Other partof the project involve NMR technics to provide assignment and determination of proteinstructure.

National Category
Chemical Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-357809 (URN)
Conference
EMBO Course: Multidimensional NMR in Structural Biology, Joachimsthal, 12-19 Aug 2018.
Available from: 2018-08-21 Created: 2018-08-21 Last updated: 2018-08-21
Palica, K., Andersson, H. & Erdélyi, M. (2018). Development of metallo-β-lactamase inhibitors to control antibioticresistance. In: : . Paper presented at 1ST NATIONAL MEETING OF THE SWEDISH CHEMICAL SOCIETY in Lund, 17-20 June 2018.
Open this publication in new window or tab >>Development of metallo-β-lactamase inhibitors to control antibioticresistance
2018 (English)Conference paper, Poster (with or without abstract) (Refereed)
Abstract [en]

According to the recent reports of WHO,1 one of the major challenges of the XXI century isthe rapidly growing bacterial resistance against antibiotics. As a result, bacterial infectionsmay become untreatable within a considerable time giving simple infections, such aspneumonia or Septicemia, a highly probable mortal prognosis. Without access to efficientantibiotics simple surgeries, giving birth and dental interventions, for example, may becomerisky.The mostly widely spread mechanism of bacterial resistance is mediated by β-lactamases, aspecific group of enzymes responsible for the degradation or modification of antibiotics priorto reaching their bacterial target sites. Metallo-β-lactamases are the clinically mostimportant, as these cleave also carbapenems, which are the last resort antibiotics to date.Recent reports indicate that bacteria need barely three months to develop resistance againstnew antibiotics, making their development into an unattractive, high risk approach.The key point of the mechanism of antibiotics degradation by metallo-β-lactamases is thecreation of a tetrahedral intermediate (EI) upon a C–N bond cleavage (Fig. 1). This stepinvolves irreversible chemical changes, which lead to the inactivation of the β-lactamantibiotics.

This project is focused on the development of bioisosters of existing antibiotics, i.e.compounds resembling the transition state of their cleavage (Fig 1). These are expected tohave both metallo-β-lactamase inhibitory and antibiotic properties. This strategy allows forthe reactivation of existing antibiotics, and possibly the avoidance of the need forcombinatorial therapy.Further studies of interaction between NDM-1 (New Delhi Metallo-β-Lactamases-1) andsynthesized ligands will bring insights immensely valuable for the prevention of bacterialresistance against antibiotic treatment.

National Category
Chemical Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-357813 (URN)
Conference
1ST NATIONAL MEETING OF THE SWEDISH CHEMICAL SOCIETY in Lund, 17-20 June 2018
Available from: 2018-08-21 Created: 2018-08-21 Last updated: 2018-08-21
Palica, K., Andersson, H. & Erdélyi, M. (2018). Development of metallo-β-lactamase inhibitors to controlantibiotic resistance. In: : . Paper presented at 16th International School of Biological Magnetic Resonance Course: Frontiers of Biophysics, Erice, Sicily 1-8 August 2018.
Open this publication in new window or tab >>Development of metallo-β-lactamase inhibitors to controlantibiotic resistance
2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

According to WHO recent reports indicates one of the biggest problem of XXI century is rapidly growing resistance of bacteria.[1] The most powerful human counter weapon –antibiotics, starts to be an ineffective way in the treatment of bacterial infections. Soonwithout any action we can approach a point when simple infections like pneumonia orSepticemia, will carry a highly probable mortal prognosis.The mostly widely spread mechanism of bacteria resistance is the production of a specificgroup of enzymes β-lactamases, responsible for the degradation or modification of antibiotics,prior to it reaching its target side. At the moment, bacteria need around three months to develop resistance for new type of antibiotics. That is why modern treatment begin toabandon the development of new antibiotics and focuses on inhibitions of β-lactamases andquiet often on metallo-β-lactamases which spectrum is the broadest.The key point of the mechanism of antibiotics hydrolysis by metallo- β -lactamases is creationof tetrahedral intermediate (EI) as a C–N bond-cleaved species. This step indicatesirreversible chemical changes which lead to inactive product.

The aim of this project is focused on existing antibiotics, their transition states - EI andcreation of new bioisosteres, which can have both inhibition and antibiotics properties. Thisstrategy allows for the avoidance of combinatorial therapy and use medicine with widespectrum of action.Further studies of interaction between NDM-1 (New Delhi Metallo-β-Lactamases-1) and synthesized ligands will bring a highly needed and effective way to prevent resistance of bacteria.

National Category
Chemical Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-357815 (URN)
Conference
16th International School of Biological Magnetic Resonance Course: Frontiers of Biophysics, Erice, Sicily 1-8 August 2018
Available from: 2018-08-21 Created: 2018-08-21 Last updated: 2019-01-03Bibliographically approved
Danelius, E., Andersson, H., Jarvoll, P., Lood, K., Gräfenstein, J. & Erdélyi, M. (2018). Halogen bond promoted peptide folding. In: : . Paper presented at The 3rd International Symposium on Halogen Bonding, Greenville, USA, June 11-14 2018..
Open this publication in new window or tab >>Halogen bond promoted peptide folding
Show others...
2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

We have developed a β-hairpin peptide model system that permits quantitative evaluation of weak interactions in a biologically relevant environment. The influence of a single weak force was measured by detection of the extent to which it modulates peptide folding. Initially we have optimized a β-hairpin model system, using the simpler to synthesize hydrogen bonding analogues of our target system encompassing halogen bond donor and acceptor sites [1,2,3]. Using a combined computational and NMR spectroscopic ensemble analysis, we have quantified the stabilizing effect of a single secondary interaction on the folded β-hairpin conformation. We have demonstrated that a chlorine centered halogen bond, formed between two amino acid side chains in an interstrand manner (Figure 1), provides a conformational stabilization comparable to the analogous hydrogen bond [4]. The negative control, i.e. the peptide containing a noninteracting aliphatic side chain, was ~30% less folded than the hydrogen and halogen bonding analogues, revealing the high impact of the interstrand interaction on folding. The experimental results are corroborated by computation on the DFT level. This is the first report of quantification of a conformation-stabilizing chlorine centered halogen bond in a peptide system.  

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-371811 (URN)
Conference
The 3rd International Symposium on Halogen Bonding, Greenville, USA, June 11-14 2018.
Available from: 2019-01-02 Created: 2019-01-02 Last updated: 2019-01-07
Danelius, E., Andersson, H. & Erdélyi, M. (2018). Solution ensemble analysis of macrocycles. In: : . Paper presented at SMASH – Small Molecule NMR Conference, Philadelphia, Pennsylvania, USA, 16-19 september 2018.
Open this publication in new window or tab >>Solution ensemble analysis of macrocycles
2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

Macrocycles are key drug leads for protein targets with large, flat and featureless binding sites, including protein-protein interfaces.  Due to their conformational flexibility macrocycles typically exist as a mixture of interconverting geometries in solution, and hence cannot be represented by a single, averaged conformation.  This flexibility is a result of continuously forming and breaking a number of weak intramolecular interactions.  The yielded conformations in solution vastly impact the bioactivity, solubility and membrane permeability of the macrocycles.  Therefore, describing their conformational ensembles, as well as the impact of conformation stabilizing weak interactions, is of fundamental importance, and the knowledge gained is directly applicable to medicinal chemistry.

In order to describe macrocycle structure and dynamics, time-averaged solution spectroscopic data has to be deconvoluted into the present conformations along with their respective probability.  We have studied the solution ensembles of a series of macrocycles using the NAMFIS (NMR analysis of molecular flexibility in solution) algorithm.  This combined computational and spectroscopic ensembles analysis deconvolutes time averaged NMR data by identifying the real conformations and assigning them with their molar fractions.  Theoretical ensembles were predicted using Monte Carlo conformational searches with molecular mechanics minimization.  The generated ensembles, typically containing 40-150 conformers, were then used together with experimental NOE-based distances and J-coupling-based dihedral angles to identify the molar fractions of the conformations present in solution.

We applied this technique to gain understanding of weak chemical interactions in a biologically relevant environment, by analyzing macrocyclic β-hairpin peptides.  The stabilizing effect provided by an interstrand weak interaction, as compared to a reference peptide lacking this interaction, was quantified through ensemble analysis.  We have shown that a single interstrand hydrogen [1,2,3] or halogen bond (Figure 1) [4], can significantly influence the folding, and increase the population of the folded conformation by up to 40%.  The NMR results were corroborated by CD-spectroscopy and MD-calculations.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-371864 (URN)
Conference
SMASH – Small Molecule NMR Conference, Philadelphia, Pennsylvania, USA, 16-19 september 2018
Available from: 2019-01-03 Created: 2019-01-03 Last updated: 2019-01-07
Karim, A., Schulz, N., Andersson, H., Nekoueishahraki, B., Carlsson, A.-C., Sarabi, D., . . . Erdélyi, M. (2018). The three-center-four-electron tetrel bond. In: : . Paper presented at Interactions Involving Group 14 - 16 Elements as Electrophilic Sites: A World Parallel to Halogen Bond, 9th – 10th June 2018; Greenville, SC; USA.
Open this publication in new window or tab >>The three-center-four-electron tetrel bond
Show others...
2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

We present a thermodynamically stable complex that possesses a three-center-four-electron (3c4e) tetrel bond [1,2], formed by capturing a reactive carbenium ion with a bidentate Lewis base. We report NMR spectroscopic, titration calorimetric and reaction kinetic evidences for the structure of this pentacoordinate species and discuss the properties of its tetrel bond, [N˜˜˜∙∙∙C∙∙∙˜˜˜N]+, in comparison with the analogous halogen, [N˜˜˜∙∙∙X∙∙∙˜˜˜N]+ and hydrogen, [N∙∙∙˜˜˜H∙∙∙˜˜˜N]+, bonds [3]. The necessity of the involvement of a bidentate Lewis base for the formation of a stable 3c4e tetrel bond is demonstrated by providing spectroscopic and crystallographic evidence, that a monodentate Lewis base induces a reaction rather than stabilizing the reactive species. A vastly decreased Lewis basicity of the bidentate ligand or reduced Lewis acidity of the carbenium ion weakens — or even prohibits — the formation of the pentacoordinate species, whereas synthetic modifications facilitating attractive orbital overlaps promote it. As the geometry of the pentacoordinate complex resembles the SN2 transition state, it may provide a model system for the investigation of fundamental reaction mechanisms and chemical bonding theories [4].

References

1. G.C. Pimentel J. Chem. Phys. 1951, 19, 446-448

2. R.H. Crabtree Chem. Soc. Rev. 2017, 46, 1720-1729.

3. S.B. Hakkert, M. Erdelyi J. Phys. Org. Chem. 2015, 95, 2572-2578

4. Karim, N. Schultz, H. Andersson, B. Nekoueishahraki et al, 2018, submitted.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-371866 (URN)
Conference
Interactions Involving Group 14 - 16 Elements as Electrophilic Sites: A World Parallel to Halogen Bond, 9th – 10th June 2018; Greenville, SC; USA
Available from: 2019-01-03 Created: 2019-01-03 Last updated: 2019-01-07
Andersson, H., Danelius, E., Jarvoll, P., Niebling, S., Hughes, A. J., Westenhoff, S., . . . Erdélyi, M. (2017). Assessing the Ability of Spectroscopic Methods to Determine the Difference in the Folding Propensities of Highly Similar β-Hairpins. ACS omega, 2(2), 508-516
Open this publication in new window or tab >>Assessing the Ability of Spectroscopic Methods to Determine the Difference in the Folding Propensities of Highly Similar β-Hairpins
Show others...
2017 (English)In: ACS omega, ISSN 2470-1343, Vol. 2, no 2, p. 508-516Article in journal (Refereed) Published
Abstract [en]

We have evaluated the ability of nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopies to describe the difference in the folding propensities of two structurally highly similar cyclic β-hairpins, comparing the outcome to that of molecular dynamics simulations. NAMFIS-type NMR ensemble analysis and CD spectroscopy were observed to accurately describe the consequence of altering a single interaction site, whereas a single-site 13C NMR chemical shift melting curve-based technique was not.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-346688 (URN)10.1021/acsomega.6b00484 (DOI)28261689 (PubMedID)
Available from: 2018-03-20 Created: 2018-03-20 Last updated: 2018-04-05Bibliographically approved
Diwakarla, S., Nylander, E., Grönbladh, A., Reddy Vanga, S., Shamsudin Khan, Y., Gutierrez-de-Teran, H., . . . Hallberg, M. (2016). Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density. Molecular Pharmacology, 89(4), 413-424
Open this publication in new window or tab >>Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density
Show others...
2016 (English)In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, no 4, p. 413-424Article in journal (Refereed) Published
Abstract [en]

Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-275166 (URN)10.1124/mol.115.102533 (DOI)000370935700003 ()26769413 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-01-31 Created: 2016-01-31 Last updated: 2018-03-20
Andersson, H. & Hallberg, M. (2012). Discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers. International Journal of Hypertension, 2012, 789671
Open this publication in new window or tab >>Discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers
2012 (English)In: International Journal of Hypertension, ISSN 2090-0384, Vol. 2012, p. 789671-Article, review/survey (Refereed) Published
Abstract [en]

The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.

Keywords
3 (1 biphenyl 4 ylmethyl 3 ethoxycarbonyl 1 butylcarbamoyl)propionic acid plus valsartan, aldosterone, aliskiren, aminopeptidase, angiotensin, angiotensin 1 receptor antagonist, angiotensin 2 receptor antagonist, angiotensin II, angiotensin II [3-8], azilsartan medoxomil, benazepril, candesartan hexetil, captopril, dipeptidyl carboxypeptidase inhibitor, enalapril, hfi 419, hfi 435, insulin regulated aminopeptidase, insulin regulated aminopeptidase inhibitor, lisinopril, losartan, perindopril, pnb 0408, proteinase inhibitor, quinapril, ramipril, renin, renin inhibitor, saralasin, unclassified drug, unindexed drug, ageusia, antihypertensive activity, antiinflammatory activity, binding affinity, blood brain barrier, brain function, cognition, conformational transition, cyclization, drug eruption, drug half life, drug penetration, drug potency, drug research, drug structure, drug synthesis, drug targeting, human, hypertension, hypothesis, learning, memory consolidation, nonhuman, phase 2 clinical trial (topic), phase 3 clinical trial (topic), priority journal, protein interaction, renin angiotensin aldosterone system, review, structure activity relation, vasodilatation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-195409 (URN)10.1155/2012/789671 (DOI)
Available from: 2013-02-25 Created: 2013-02-25 Last updated: 2018-03-20
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3798-3322

Search in DiVA

Show all publications

Profile pages

UU profile pageORCID