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Larsson, Andreas
Publications (10 of 11) Show all publications
Nilsson, L., Larsson, A., Begum, A., Iakovleva, I., Carlsson, M., Kristoffer, B., . . . Olofsson, A. (2016). Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity. PLoS ONE, 11(4), Article ID e0153112.
Open this publication in new window or tab >>Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153112Article in journal (Refereed) Published
Abstract [en]

Amyloid formation of the plasma protein transthyretin (TTR) has been linked to familial amyloid polyneuropathy and senile systemic amyloidosis. Binding of ligands within its natural hormone binding site can stabilize the tetrameric structure and impair amyloid formation. We have recently shown that the flavonoid luteolin stabilizes TTR in human plasma with a very high selectivity. Luteolin, however, is inactivated in vivo via glucuronidation for which the preferred site is the hydroxy group at position 7 on its aromatic A-ring. We have evaluated the properties of two luteolin variants in which the 7-hydroxy group has been exchanged for a chlorine (7-Cl-Lut) or a methoxy group (7-MeO-Lut). Using an in vitro model, based on human liver microsomes, we verified that these modifications increase the persistence of the drug. Crystal structure determinations show that 7-Cl-Lut binds similarly to luteolin. The larger MeO substituent cannot be accommodated within the same space as the chlorine or hydroxy group and as a result 7-MeO-Lut binds in the opposite direction with the methoxy group in position 7 facing the solvent. Both 7-Cl-Lut and 7-MeO-Lut qualify as high-affinity binders, but in contrast to luteolin, they display a highly non-specific binding to other plasma components. The binding of the two conformations and the key-interactions to TTR are discussed in detail. Taken together, these results show a proof-of-concept that the persistence of luteolin towards enzymatic modification can be increased. We reveal two alternative high-affinity binding modes of luteolin to TTR and that modification in position 7 is restricted only to small substituents if the original orientation of luteolin should be preserved. In addition, the present work provides a general and convenient method to evaluate the efficacy of TTR-stabilizing drugs under conditions similar to an in vivo environment.

Place, publisher, year, edition, pages
Public Library Science, 2016
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-119997 (URN)10.1371/journal.pone.0153112 (DOI)000373603500101 ()27050398 (PubMedID)
Available from: 2016-05-04 Created: 2016-05-04 Last updated: 2018-06-07Bibliographically approved
Lindgren, A. E., Larsson, A., Linusson, A. & Elofsson, M. (2014). Statistical molecular design: a tool to follow up hits from small-molecule screening.. Methods in Molecular Biology, 1056, 169-188
Open this publication in new window or tab >>Statistical molecular design: a tool to follow up hits from small-molecule screening.
2014 (English)In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1056, p. 169-188Article in journal (Refereed) Published
Abstract [en]

In high-throughput screening (HTS) a robust assay is used to interrogate a large collection of small organic molecules in order to find compounds, hits, with a desired biological activity. The hits are then further explored by an iterative process where new compounds are designed, purchased, or synthesized, followed by an evaluation in one or more assays. Statistical molecular design (SMD) is a useful method to select a balanced, varied, and information-rich compound collection based on hits from HTS in order to create a foundation for development of optimized compounds with improved properties. In this chapter, we describe the use of SMD to explore a hit obtained from small-molecule screening.

Place, publisher, year, edition, pages
Springer, 2014
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-85440 (URN)10.1007/978-1-62703-592-7_17 (DOI)24306873 (PubMedID)
Available from: 2014-02-04 Created: 2014-02-04 Last updated: 2018-06-08Bibliographically approved
Nordstrand, A., Lundholm, M., Larsson, A., Lerner, U. H., Widmark, A. & Wikström, P. (2013). Inhibition of the insulin-like growth factor-1 receptor enhances effects of Simvastatin on prostate cancer cells in co-culture with bone. Cancer Microenvironment, 6(3), 231-240
Open this publication in new window or tab >>Inhibition of the insulin-like growth factor-1 receptor enhances effects of Simvastatin on prostate cancer cells in co-culture with bone
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2013 (English)In: Cancer Microenvironment, ISSN 1875-2292, E-ISSN 1875-2284, Vol. 6, no 3, p. 231-240Article in journal (Refereed) Published
Abstract [en]

Prostate cancer (PC) bone metastases show weak responses to conventional therapies. Bone matrix is rich in growth factors, with insulin-like growth factor-1 (IGF-1) being one of the most abundant. IGF-1 acts as a survival factor for tumor cells and we speculate that bone-derived IGF-1 counteracts effects of therapies aimed to target bone metastases and, consequently, that therapeutic effects could be enhanced if given in combination with IGF-1 receptor (IGF-1R) inhibitors. Simvastatin inhibits the mevalonate pathway and has been found to induce apoptosis of PC cells. The aims of this study were to confirm stimulating effects of bone-derived IGF-1 on PC cells and to test if IGF-1R inhibition enhances growth inhibitory effects of simvastatin on PC cells in a bone microenvironment. The PC-3 and 22Rv1 tumor cell lines showed significantly induced cell growth when co-cultured with neonatal mouse calvarial bones. The tumor cell IGF-1R was activated by calvariae-conditioned media and neutralization of bone-derived IGF-1 abolished the calvarium-induced PC-3 cell growth. Treatment of PC-3 and 22Rv1 cells with simvastatin, or the IGF-1R inhibitor NVP-AEW541, reduced tumor cell numbers and viability, and induced apoptosis. Combined simvastatin and NVP-AEW541 treatment resulted in enhanced growth inhibitory effects compared to either drug given alone. Effects of simvastatin involved down-regulation of IGF-1R in PC-3 and of constitutively active androgen receptor variants in 22Rv1 cells. In conclusion, we suggest that IGF-1 inhibition may be a way to strengthen effects of apoptosis-inducing therapies on PC bone metastases; a possibility that needs to be further tested in pre-clinical models.

Place, publisher, year, edition, pages
Springer, 2013
Keywords
Prostate cancer, Bone metastases, IGF-1R, Simvastatin, Cholesterol
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-65834 (URN)10.1007/s12307-013-0129-z (DOI)23335094 (PubMedID)
Available from: 2013-02-12 Created: 2013-02-12 Last updated: 2018-06-08Bibliographically approved
Edvinsson, S., Johansson, S. & Larsson, A. (2012). An efficient procedure for the synthesis of formylacetic esters. Tetrahedron Letters, 53(50), 6819-6821
Open this publication in new window or tab >>An efficient procedure for the synthesis of formylacetic esters
2012 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 53, no 50, p. 6819-6821Article in journal (Refereed) Published
Abstract [en]

An efficient synthesis of formylacetic esters via ozonolysis of trans-beta-hydromuconic esters followed by a solid-supported triphenylphosphine reduction has been developed. In addition, an extension toward formylacetic amides and a one-pot preparation of more stable intermediates which can be used for further transformations are also described.

Keywords
Formylacetic esters, Ozonolysis, Solid phase scavenging, Heterocycles
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-63010 (URN)10.1016/j.tetlet.2012.10.021 (DOI)000311473500022 ()
Available from: 2013-01-02 Created: 2012-12-27 Last updated: 2018-06-08Bibliographically approved
Hanessian, S., Larsson, A., Fex, T., Knecht, W. & Blomberg, N. (2010). Design and synthesis of macrocyclic indoles targeting blood coagulation cascade Factor XIa. Bioorganic & Medicinal Chemistry Letters, 20(23), 6925-6928
Open this publication in new window or tab >>Design and synthesis of macrocyclic indoles targeting blood coagulation cascade Factor XIa
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2010 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 20, no 23, p. 6925-6928Article in journal (Refereed) Published
Abstract [en]

The synthesis of a series of novel macrocyclic compounds designed to target blood coagulation Factor XIa is described. The compounds were evaluated for their inhibition of a small set of serine proteases. Several compounds displayed modest activity and good selectivity for Factor XIa. Within the series, a promising lead structure for developing novel macrocyclic inhibitors of thrombin was identified.

Place, publisher, year, edition, pages
Elsevier Ltd, 2010
Keywords
Enzyme inhibitor, Thrombin, Macrocycle
Identifiers
urn:nbn:se:umu:diva-38058 (URN)10.1016/j.bmcl.2010.09.141 (DOI)000283801400010 ()21035339 (PubMedID)
Available from: 2010-11-24 Created: 2010-11-24 Last updated: 2018-06-08Bibliographically approved
Auzzas, L., Larsson, A., Matera, R., Baraldi, A., Deschênes-Simard, B., Giannini, G., . . . Hanessian, S. (2010). Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity. Journal of Medicinal Chemistry, 53(23), 8387-8399
Open this publication in new window or tab >>Non-natural macrocyclic inhibitors of histone deacetylases: design, synthesis, and activity
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 23, p. 8387-8399Article in journal (Refereed) Published
Abstract [en]

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors.

Place, publisher, year, edition, pages
American Chemical Society, 2010
Identifiers
urn:nbn:se:umu:diva-38059 (URN)10.1021/jm101092u (DOI)000284738400018 ()21073160 (PubMedID)
Available from: 2010-11-29 Created: 2010-11-24 Last updated: 2018-06-08Bibliographically approved
Hanessian, S., Auzzas, L., Larsson, A., Zhang, J., Giannini, G., Gallo, G., . . . Cabri, W. (2010). Vorinostat-like molecules as structural, stereochemical, and pharmacological tools. ACS Medicinal Chemical Letters, 1(2), 70-74
Open this publication in new window or tab >>Vorinostat-like molecules as structural, stereochemical, and pharmacological tools
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2010 (English)In: ACS Medicinal Chemical Letters, ISSN 1948-5875, Vol. 1, no 2, p. 70-74Article in journal (Refereed) Published
Abstract [en]

The inhibitory activity of an ω-alkoxy analogue of the HDAC inhibitor, Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with regard to structural biology information retrieved through computational methods. Preliminary absorption and metabolism studies were performed, which positioned this compound as a potential candidate for further preclinical studies and delineated measures for improving its pharmacokinetic profile.

Place, publisher, year, edition, pages
American Chemical Society, 2010
Keywords
HDAC promiscuous inhibitors, SAHA analogues, HDAC1-11 profile, class IIa-specific profile, absorption and metabolism
Identifiers
urn:nbn:se:umu:diva-38185 (URN)10.1021/ml100028g (DOI)000281134500005 ()
Available from: 2010-11-29 Created: 2010-11-29 Last updated: 2018-06-08Bibliographically approved
Larsson, A., Johansson, S. M. C., Pinkner, J. S., Hultgren, S. J., Almqvist, F., Kihlberg, J. & Linusson, A. (2005). Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli. Journal of Medicinal Chemistry, 48(4), 935-945
Open this publication in new window or tab >>Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli
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2005 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 4, p. 935-945Article in journal (Refereed) Published
Abstract [en]

A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein(-)protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2005
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-13553 (URN)10.1021/jm040818l (DOI)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2018-06-09Bibliographically approved
Larsson, A. (2004). Antiadhesive agents targeting uropathogenic Escherichia coli: Multivariate studies of protein-protein and protein-carbohydrate interactions. (Doctoral dissertation). Umeå: Kemi
Open this publication in new window or tab >>Antiadhesive agents targeting uropathogenic Escherichia coli: Multivariate studies of protein-protein and protein-carbohydrate interactions
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Antiadhesiva substanser riktade mot uropatogena Escherichia coli : Multivariata studier av protein-protein och protein-kolhydrat interaktioner
Abstract [en]

This thesis describes studies directed towards development of novel antiadhesive agents, with particular emphasis on compounds that prevent attachment of bacteria to a host-cell. Three different proteins involved in the assembly or function of adhesive pili in uropathogenic Escherichia coli have been targeted either by rational structure based design or statistical molecular methods.

A library of substituted galabiose (Galα1-4Gal) derivatives was screened for binding to the E. coli adhesin PapG in an assay based on surface plasmon resonance, and for inhibition of Streptococcus suis adhesins PN and PO in a hemagglutination assay. The results were used to generate QSAR models which had good predictive powers and provided further insight in the structural requirements needed for high affinity binding.

2-pyridones and amino acid derivatives were modelled into the binding site of chaperones involved in pilus assembly in E. coli and a heuristic method, VALIDATE, was used for affinity prediction. The affinity of the compounds for the chaperones PapD and FimC were assessed in assays based on surface plasmon resonance and relaxation-edited NMR spectroscopy. Their ability to disrupt chaperone/subunit complexes was investigated in vitro through a FPLC assay and their capacity to inhibit pilus formation in vivo was determined via hemagglutination and confirmed with atomic force microscopy.

Statistical molecular design was used to design a diverse peptide library targeting pili subunits, and an ELISA was developed to investigate the ability of the peptides to inhibit chaperone/subunit complexation. The resulting QSAR model provided extensive information regarding binding of the peptides to the subunits. Because the peptides were suggested to bind in an extended β-strand formation, β-strand mimetics consisting of oligomeric enaminones were designed. Finally, new methods to synthesize enaminone building blocks were developed using microwave assisted chemistry.

The projects described have generated compounds that besides their value as leads for developing novel antibacterial agents, also constitute new chemical tools to study the mechanisms underlying bacterial virulence.

Place, publisher, year, edition, pages
Umeå: Kemi, 2004. p. 92
Keywords
Organic chemistry, Antibacterial, pili, antiadhesive agents, structure based design, statistical molecular design, 2-pyridone, amino acid derivative, galabiose, enaminone, SPR, ELISA, QSAR, Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-314 (URN)91-7305-731-2 (ISBN)
Public defence
2004-10-01, KB3B1, KBC, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2004-09-13 Created: 2004-09-13 Last updated: 2018-06-09Bibliographically approved
Larsson, A., Ohlsson, J., Dodson, K. W., Hultgren, S. J., Nilsson, U. & Kihlberg, J. (2003). Quantitative studies of the binding of the class II PapG adhesin from Uropathogenic Escherichia coli to oligosaccharides.. Bioorganic & Medicinal Chemistry, 11(10), 2255-2261
Open this publication in new window or tab >>Quantitative studies of the binding of the class II PapG adhesin from Uropathogenic Escherichia coli to oligosaccharides.
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2003 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 10, p. 2255-2261Article in journal (Refereed) Published
Abstract [en]

Binding of the class II PapG adhesin, found at the tip of filamentous pili on Escherichia coli, to the carbohydrate moiety of globoseries glycolipids in the human kidney is a key step in development of pyelonephritis, a severe form of urinary tract infection. An assay based on surface plasmon resonance for quantification of the binding of the class II PapG adhesin to oligosaccharides has been developed. Using this assay dissociation constants ranging from 80 to 540 μM were determined for binding of the PapG adhesin to di-pentasaccharide fragments from the globoseries of glycolipids. A series of galabiose derivatives, modified at the anomeric position, O-2′ or O-3′, was also investigated. The anomeric position appeared to be the most promising for development of improved inhibitors of PapG-mediated adhesion of E. colip-Methoxyphenyl galabioside was found to be most potent (Kd=140 μM), and binds to PapG almost as well as the Forssman pentasaccharide.

Place, publisher, year, edition, pages
Elsevier, 2003
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-4090 (URN)10.1016/S0968-0896(03)00114-7 (DOI)
Available from: 2004-09-13 Created: 2004-09-13 Last updated: 2018-06-09Bibliographically approved
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