Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Salanti, Ali; Clausen, Thomas; Agerbæk, Mette Ø.; Nakouzi, Nader Al; Dahlbäck, Madeleine; Oo, Htoo Zarni; Sherry, Lance; Gustavsson, Tobias; Rich, Justin; Hedberg, Bradley J.; Mao, Yang; Barington, Line; Pereira, Marina Ayres; LoBello, Janine; Endo, Makoto; Fazli, Ladan; Soden, Jo; Wang, Chris Kedong; Sander, Adam F.; Dagil, Robert; Thrane, Susan; Holst, Peter Johannes; Meng, Le; Favero, Francesco; Weiss, Glen J.; Nielsen, Morten A; Freeth, Jim; Nielsen, Torsten O.; Zaia, Joseph; Tran, Nhan L.; Trent, Jeff; Babcook, John S.; Theander, Thor G.; Sorensen, Poul H.; Daugaard, Mads

doi:10.1016/j.ccell.2015.09.003

Cited by 169 publications

(276 citation statements)

References 26 publications

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“…The recombinant ID1-DBL2X-ID2a region of VAR2CSA protein (rVAR2) and the control protein (rDBL4) containing V5 tag at the C-terminals were prepared in E. coli as described previously [24]. Briefly.…”

Section: Production Of Recombinant Var2csa Proteinsmentioning

confidence: 99%

Molecular dissection of placental malaria protein VAR2CSA interaction with a chemo-enzymatically synthesized chondroitin sulfate library

et al. 2016

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Placental malaria, a serious infection caused by the parasite Plasmodium falciparum, is characterized by the selective accumulation of infected erythrocytes (IEs) in the placentas of the pregnant women. Placental adherence is mediated by the malarial VAR2CSA protein, which interacts with chondroitin sulfate (CS) proteoglycans present in the placental tissue. CS is a linear acidic polysaccharide composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-galactosamine that are modified by sulfate groups at different positions. Previous reports have shown that placental-adhering IEs were associated with an unusually low sulfated form of chondroitin sulfate A (CSA) and that a partially sulfated dodecasaccharide is the minimal motif for the interaction. However, the fine molecular structure of this CS chain remains unclear. In this study, we have characterized the CS chain that interacts with a recombinant minimal CS-binding region of VAR2CSA (rVAR2) using a CS library of various defined lengths and sulfate compositions. The CS library was chemo-enzymatically synthesized with bacterial chondroitin polymerase and recombinant CS sulfotransferases. We found that C-4 sulfation of the N-acetyl-D-galactosamine residue is critical for supporting rVAR2 binding, whereas no other sulfate modifications showed effects. Interaction of rVAR2 with CS is highly correlated with the degree of C-4 sulfation and CS chain length. We confirmed that the minimum structure binding to rVAR2 is a tri-sulfated CSA dodecasaccharide, and found that a highly sulfated CSA eicosasaccharide is a more potent inhibitor of rVAR2 binding than the dodecasaccharides. These results suggest that CSA derivatives may potentially serve as targets in therapeutic strategies against placental malaria.

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Section: Production Of Recombinant Var2csa Proteinsmentioning

confidence: 99%

Molecular dissection of placental malaria protein VAR2CSA interaction with a chemo-enzymatically synthesized chondroitin sulfate library

et al. 2016

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“…CS-E has been proposed to be involved in ovarian cancer tumorigenesis as it mediates binding of the vascular endothelial growth factor (VEGF) (27,33). More recently, the malaria protein VAR2CSA was shown to bind a form of CS-A that is both expressed in the placenta and various cancers, especially on cancer-associated proteoglycans including CD44 and CSPG but not on healthy tissues (35). These findings suggest that detection of defined isoforms of CS can be a useful diagnostic in monitoring cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Structure–function characterization of three human antibodies targeting the vaccinia virus adhesion molecule D8

Matho¹,

Schlossman²,

Gilchuk

et al. 2018

Journal of Biological Chemistry

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Vaccinia virus (VACV) envelope protein D8 is one of three glycosaminoglycan adhesion molecules and binds to the linear polysaccharide chondroitin sulfate (CS). D8 is also a target for neutralizing antibody responses that are elicited by the smallpox vaccine, which has enabled the first eradication of a human viral pathogen and is a useful model for studying antibody responses. However, to date, VACV epitopes targeted by human antibodies have not been characterized at atomic resolution. Here, we characterized the binding properties of several human anti-D8 antibodies and determined the crystal structures of three VACV-MAb variants, VACV-66, VACV-138, and VACV-304, separately bound to D8. While all these antibodies bound D8 with high affinity and were moderately neutralizing in the presence of complement, VACV-138 and VACV-304 also fully blocked D8 binding to CS-A, the low affinity ligand for D8. VACV-138 also abrogated D8 binding to the high-affinity ligand CS-E, but we observed residual CS-E binding was observed in the presence of VACV-304. Analysis of the VACV-138 and VACV-304 binding sites along the CS binding crevice of D8, combined with different efficiencies of blocking D8 adhesion to CS-A and CS-E allowed us to propose that D8 has a high and low affinity CS binding region within its central crevice. The crevice is amenable to protein engineering to further enhance both specificity and affinity of binding to CS-E. Finally, a wild-type D8 tetramer specifically bound to structures within the developing glomeruli of the kidney, which express CS-E. We propose that through structure-based protein engineering, an improved D8 tetramer Human antibody responses to vaccinia virus D82 could be used as a potential diagnostic tool to detect expression of CS-E, which is a possible biomarker for ovarian cancer.Smallpox is caused by infection with variola virus and was a major health threat until successful global vaccination efforts led to its complete eradication from the general human population (1). This eradication of an infectious agent was achieved by immunizing with Vaccinia virus (VACV), a related orthopoxvirus with low virulence and the active ingredient in the smallpox vaccine (2,3). Immunization with VACV leads to the robust production of highly neutralizing antibodies targeting several VACV envelope proteins, including A27, A33, B5, D8, H3, L1, and others, which are expressed on different viral envelopes (3,4). A27, D8, H3 and L1 are expressed on the outer membrane of the intracellular mature virion (IMV), while A33 and B5 are found in the more fragile extracellular enveloped virion (EEV), which has an additional host cell derived envelope. Both the IMV and the EEV particles are infectious virions, with IMV being more abundant and mainly responsible for spread between hosts, and EEV being involved in cell-to-cell spread within the host after infection with the IMV (5). As a result, a potent antibody-mediated immune response against VACV targets both infectious virions.Among the targeted envelope prote...

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“…CS levels can predict prostate cancer progression and are increased in metastatic disease (Ricciardelli et al 1997(Ricciardelli et al , 2009a. Targeting oncofoetal CS using glycosaminoglycan binding malaria protein inhibits PC3 cell growth in mouse models (Salanti et al 2015) CHPF Chondroitin sulfate synthesis CS is a key molecule in cancer progression (Theocharis et al 2006). The large CS proteoglycan Versican is linked to poor prognosis in many different cancer types (Ricciardelli et al 2009b).…”

Section: :3mentioning

confidence: 99%

“…The CSGALNACT1 enzyme is upregulated in prostate cancer cells and has been shown to be essential for prostate cancer cell viability, making it an attractive therapeutic target . Recent data suggest that targeting oncofoetal CS using glycosaminoglycan-binding malaria protein can inhibit the growth of PC3 prostate cancer cells in mouse models (Salanti et al 2015) (as PC3 cells are an AR-negative prostate cancer cell line, it will be interesting to explore this finding further in a range of AR-negative and -positive cell types).…”

Section: Chondroitin Sulfate Synthesismentioning

confidence: 99%

“…Glycans also likely play roles in all aspects of cancer progression and are therefore attractive targets for therapeutic intervention (Pinho & Reis 2015, Munkley et al 2016a. Glycans that hold particular promise as therapeutic targets in prostate cancer include chondroitin sulfate (Salanti et al 2015), the F77 antigen , SLe X (Hagisawa et al 2005) and STn (Munkley & Elliott 2016b). An increased understanding of how glycosylation modulates the biological function of prostate cancer cells will allow the development of a relatively unexploited field of drugs based on inhibitors, glycan antagonists and glycan function modulators.…”

Section: :3mentioning

confidence: 99%

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Glycosylation is a global target for androgen control in prostate cancer cells

Munkley¹

2017

Endocrine-Related Cancer

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Changes in glycan composition are common in cancer and can play important roles in all of the recognised hallmarks of cancer. We recently identified glycosylation as a global target for androgen control in prostate cancer cells and further defined a set of 8 glycosylation enzymes (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3), which are also significantly upregulated in prostate cancer tissue. These 8 enzymes are under direct control of the androgen receptor (AR) and are linked to the synthesis of important cancer-associated glycans such as sialyl-Tn (sTn), sialyl LewisX (SLeX), O-GlcNAc and chondroitin sulfate. Glycosylation has a key role in many important biological processes in cancer including cell adhesion, migration, interactions with the cell matrix, immune surveillance, cell signalling and cellular metabolism. Our results suggest that alterations in patterns of glycosylation via androgen control might modify some or all of these processes in prostate cancer. The prostate is an abundant secretor of glycoproteins of all types, and alterations in glycans are, therefore, attractive as potential biomarkers and therapeutic targets. Emerging data on these often overlooked glycan modifications have the potential to improve risk stratification and therapeutic strategies in patients with prostate cancer.

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Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Cited by 169 publications

References 26 publications

Molecular dissection of placental malaria protein VAR2CSA interaction with a chemo-enzymatically synthesized chondroitin sulfate library

Molecular dissection of placental malaria protein VAR2CSA interaction with a chemo-enzymatically synthesized chondroitin sulfate library

Structure–function characterization of three human antibodies targeting the vaccinia virus adhesion molecule D8

Glycosylation is a global target for androgen control in prostate cancer cells

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