BIOGNOS AB

Göteborg, Sweden

BIOGNOS AB

Göteborg, Sweden

Time filter

Source Type

Battistel M.D.,U.S. Food and Drug Administration | Azurmendi H.F.,U.S. Food and Drug Administration | Frank M.,Biognos AB | Freedberg D.I.,U.S. Food and Drug Administration
Journal of the American Chemical Society | Year: 2015

We describe the direct NMR detection of a C-H···O nonconventional hydrogen bond (Hbond) and provide experimental and theoretical evidence for conventional Hbonds in the pentasaccharide sialyl Lewis-X (sLeX-5) between 5 and 37 °C in water. Extensive NMR structural studies together with molecular dynamics simulations offer strong evidence for significant local dynamics in the LeX core and for previously undetected conventional Hbonds in rapid equilibrium that modulate structure. These NMR studies also showed temperature-dependent 1H and 13C line broadening. The resulting model emerging from this study is more complex than a simple rigid core description of LeX-like molecules and improves our understanding of stabilizing interactions in glycans. © 2015 American Chemical Society.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2013-ITN | Award Amount: 3.45M | Year: 2013

Protozoan parasites and helminths are the cause of some of the most devastating diseases worldwide and a major effort is needed to be able to control or eliminate these diseases. Glycoconjugates are abundant and ubiquitous on the surface of many parasites and they are frequently involved in their survival strategies by forming a protective barrier against host defences. A common feature of the parasites cell surface architecture is the presence of an elaborate and often highly decorated glycocalyx that allows it to interact and respond to the external environment. Therefore, the study of the glycobiology of these organisms offers unique opportunities to devise novel strategies to tackle parasitic-caused diseases. However, the exquisite diversity of these glycoconjugates and of their biosynthetic machineries, the difficulties related with their structural analysis and the complexity associated with their synthesis in the laboratory, poses a tremendous challenge for the scientific community. To address these challenges GlycoPar proposes to establish a European based training programme in a world-class collaborative research environment steered by some of the world leaders in the fast evolving field of parasite glycobiology, in close association with European industrial enterprises. The researchers recruited through this initiative will be exposed, both at the local and network-wide level, to a multicultural and highly multidisciplinary PhD training. This programme will acquaint them with a complete range of state-of-the-art glycobiology methodologies, alongside with valuable transferable and entrepreneurial skills. All together the aim is to create a PhD-level trained generation of young scientists capable of tackling the challenges that parasite glycobiology implies with improved career prospects and employability as well as preparing them to become future leaders in research institutions and industry.


Neu U.,University of Tübingen | Neu U.,UK National Institute for Medical Research | Allen S.-a.A.,Brown University | Blaum B.S.,University of Tübingen | And 10 more authors.
PLoS Pathogens | Year: 2013

Viruses within a family often vary in their cellular tropism and pathogenicity. In many cases, these variations are due to viruses switching their specificity from one cell surface receptor to another. The structural requirements that underlie such receptor switching are not well understood especially for carbohydrate-binding viruses, as methods capable of structure-specificity studies are only relatively recently being developed for carbohydrates. We have characterized the receptor specificity, structure and infectivity of the human polyomavirus BKPyV, the causative agent of polyomavirus-associated nephropathy, and uncover a molecular switch for binding different carbohydrate receptors. We show that the b-series gangliosides GD3, GD2, GD1b and GT1b all can serve as receptors for BKPyV. The crystal structure of the BKPyV capsid protein VP1 in complex with GD3 reveals contacts with two sialic acid moieties in the receptor, providing a basis for the observed specificity. Comparison with the structure of simian virus 40 (SV40) VP1 bound to ganglioside GM1 identifies the amino acid at position 68 as a determinant of specificity. Mutation of this residue from lysine in BKPyV to serine in SV40 switches the receptor specificity of BKPyV from GD3 to GM1 both in vitro and in cell culture. Our findings highlight the plasticity of viral receptor binding sites and form a template to retarget viruses to different receptors and cell types. © 2013 Neu et al.


Kumar S.,German Cancer Research Center | Frank M.,Biognos AB | Schwartz-Albiez R.,German Cancer Research Center
PLoS ONE | Year: 2013

Human Galectin-8 (Gal-8) is a member of the galectin family which shares an affinity for β-galactosides. The tandem-repeat Gal-8 consists of a N- and a C-terminal carbohydrate recognition domain (N- and C-CRD) joined by a linker peptide of various length. Despite their structural similarity both CRDs recognize different oligosaccharides. While the molecular requirements of the N-CRD for high binding affinity to sulfated and sialylated glycans have recently been elucidated by crystallographic studies of complexes with several oligosaccharides, the binding specificities of the C-CRD for a different set of oligosaccharides, as derived from experimental data, has only been explained in terms of the three-dimensional structure for the complex C-CRD with lactose. In this study we performed molecular dynamics (MD) simulations using the recently released crystal structure of the Gal-8C-CRD to analyse the three-dimensional conditions for its specific binding to a variety of oligosaccharides as previously defined by glycan-microarray analysis. The terminal β-galactose of disaccharides (LacNAc, lacto-N-biose and lactose) and the internal β-galactose moiety of blood group antigens A and B (BGA, BGB) as well as of longer linear oligosaccharide chains (di-LacNAc and lacto-N-neotetraose) are interacting favorably with conserved amino acids (H53, R57, N66, W73, E76). Lacto-N-neotetraose and di-LacNAc as well as BGA and BGB are well accommodated. BGA and BGB showed higher affinity than LacNAc and lactose due to generally stronger hydrogen bond interactions and water mediated hydrogen bonds with α1-2 fucose respectively. Our results derived from molecular dynamics simulations are able to explain the glycan binding specificities of the Gal-8C-CRD in comparison to those of the Gal-8N -CRD. © 2013 Kumar et al.


Zocher G.,University of Tübingen | Mistry N.,Umeå University | Frank M.,Biognos AB | Hahnlein-Schick I.,University of Tübingen | And 4 more authors.
PLoS Pathogens | Year: 2014

The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 Å resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for α2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that α2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC. © 2014 Zocher et al.


Frank M.,Biognos AB | Walker R.C.,University of California at San Diego | Lanzilotta W.N.,University of Georgia | Prestegard J.H.,University of Georgia | Barb A.W.,Iowa State University
Journal of Molecular Biology | Year: 2014

The fragment crystallizable (Fc) region links the key pathogen identification and destruction properties of immunoglobulin G (IgG). Pathogen opsonization positions Fcs to activate pro-inflammatory Fcγ receptors (FcγRs) on immune cells. The cellular response and committal to a damaging, though protective, immune response are tightly controlled at multiple levels. Control mechanisms are diverse and in many cases unclear, but one frequently suggested contribution originates in FcγR affinity being modulated through shifts in Fc conformational sampling. Here, we report a previously unseen IgG1 Fc conformation. This observation motivated an extensive molecular dynamics investigation of polypeptide and glycan motions that revealed greater amplitude of motion for the N-terminal Cγ2 domains and N-glycan than previously observed. Residues in the Cγ2/Cγ3 interface and disulfide-bonded hinge were identified as influencing the Cγ2 motion. Our results are consistent with a model of Fc that is structurally dynamic. Conformational states that are competent to bind immune-stimulating FcγRs interconverted with Fc conformations distinct from those observed in FcγR complexes, which may represent a transient, nonbinding population. © 2014 Elsevier Ltd.


Nasir W.,Gothenburg University | Frank M.,Biognos AB. | Koppisetty C.A.K.,Biognos AB. | Koppisetty C.A.K.,Chalmers University of Technology | And 3 more authors.
Glycobiology | Year: 2012

Human noroviruses cause recurrent epidemics of gastroenteritis known to be dominated by the clinically important GII.4 genotype which recognizes human Secretor gene-dependent ABH histo-blood group antigens (HBGAs) as attachment factors. There is increasing evidence that GII.4 noroviruses have undergone evolutionary changes to recognize Lewis antigens and non-Secretor saliva. In this study, we have investigated the possibilities of the Lewis 1,3/1,4 fucoses as mediators of binding of GII.4 noroviruses to Lewis antigens. The study was carried out using molecular dynamics simulations of Lewis type-1 and type-2 chain HBGAs in complex with VA387 P domain dimers in explicit water. Based on the computer simulations, we suggest the possibility of two receptor binding modes for Lewis HBGAs: the "Secretor pose" with the Secretor Fuc1,2 in the binding site and the "Lewis pose" with the Lewis Fuc1,3/1,4 residues in the binding site. This was further supported by an extensive GlyVicinity analysis of the Protein Data Bank with respect to the occurrence of the Lewis and Secretor poses in complexes of Lewis antigens with lectins and antibodies as well as GII norovirus strains. The Lewis pose can also explain the interactions of GII.4 norovirus strains with Lex and SLex structures. Moreover, the present model suggests binding of complex branched polysaccharides, with the Lewis antigens at the nonreducing end, to P domain dimers of GII.4 strains. Our results are relevant for understanding the evolution of norovirus binding specificities and for in silico design of future antiviral therapeutics. © 2012 The Author.


Koppisetty C.A.K.,Biognos AB | Koppisetty C.A.K.,Chalmers University of Technology | Frank M.,Biognos AB | Kemp G.J.L.,Chalmers University of Technology | And 2 more authors.
Journal of Chemical Information and Modeling | Year: 2013

Computing binding energies of protein-ligand complexes including their enthalpy and entropy terms by means of computational methods is an appealing approach for selecting initial hits and for further optimization in early stages of drug discovery. Despite the importance, computational predictions of thermodynamic components have evaded attention and reasonable solutions. In this study, support vector machines are used for developing scoring functions to compute binding energies and their enthalpy and entropy components of protein-ligand complexes. The binding energies computed from our newly derived scoring functions have better Pearson's correlation coefficients with experimental data than previously reported scoring functions in benchmarks for protein-ligand complexes from the PDBBind database. The protein-ligand complexes with binding energies dominated by enthalpy or entropy term could be qualitatively classified by the newly derived scoring functions with high accuracy. Furthermore, it is found that the inclusion of comprehensive descriptors based on ligand properties in the scoring functions improved the accuracy of classification as well as the prediction of binding energies including their thermodynamic components. The prediction of binding energies including the enthalpy and entropy components using the support vector machine based scoring functions should be of value in the drug discovery process. © 2013 American Chemical Society.


Olofsson S.,Gothenburg University | Blixt O.,Copenhagen University | Bergstrom T.,Gothenburg University | Frank M.,Biognos AB | Wandall H.H.,Copenhagen University
Reviews in Medical Virology | Year: 2016

Viral envelope glycoproteins are major targets for antibodies that bind to and inactivate viral particles. The capacity of a viral vaccine to induce virus-neutralizing antibodies is often used as a marker for vaccine efficacy. Yet the number of known neutralization target epitopes is restricted owing to various viral escape mechanisms. We expand the range of possible viral glycoprotein targets, by presenting a previously unknown type of viral glycoprotein epitope based on a short peptide stretch modified with small O-linked glycans. Besides being immunologically active, these epitopes have a high potential for antigenic variation. Thus, sera from patients infected with EBV develop individual IgG responses addressing the different possible glycopeptide glycoforms of one short peptide backbone that reflect individual variations in the course of virus infection. In contrast, in HSV type 2 meningitis patients, CSF antibodies are focussed to only one single glycoform peptide of a major viral glycoprotein. Thus, dependent on the viral disease, the serological response may be variable or constant with respect to the number of targeted peptide glycoforms. Mapping of these epitopes relies on a novel three-step procedure that identifies any reactive viral O-glycosyl peptide epitope with respect to (i) relevant peptide sequence, (ii) the reactive glycoform out of several possible glycopeptide isomers of that peptide sequence, and (iii) possibly tolerated carbohydrate or peptide structural variations at glycosylation sites. In conclusion, the viral O-glycosyl peptide epitopes may be of relevance for development of subunit vaccines and for improved serodiagnosis of viral diseases. © 2016 John Wiley & Sons, Ltd.


Frank M.,Biognos AB
Topics in Medicinal Chemistry | Year: 2014

Docking methods are a valuable tool for the prediction of carbohydrate binding sites and the design of carbohydrate-based drugs. However, there are also significant limitations and care needs to be taken when evaluating the docking results. In this chapter the challenges, limitations, and possible pitfalls in docking of carbohydrates are described. Practical examples explain the use of docking methods for the rational design of carbohydrate-based inhibitors as well as the prediction of carbohydrate binding sites. © Springer-Verlag Berlin Heidelberg 2014.

Loading BIOGNOS AB collaborators
Loading BIOGNOS AB collaborators