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Characterization of...
Characterization of bonds formed between platelet factor 4 and negatively charged drugs using single molecule force spectroscopy
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- Block, Stephan, 1978 (författare)
- Chalmers tekniska högskola,Chalmers University of Technology,Universitätsmedizin Greifswald,Greifswald University Hospital
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- Greinacher, A. (författare)
- Universitätsmedizin Greifswald,Greifswald University Hospital
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- Helm, C. A. (författare)
- Universität Greifswald,University of Greifswald
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- Delcea, M. (författare)
- Universitätsmedizin Greifswald,Greifswald University Hospital
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(creator_code:org_t)
- Royal Society of Chemistry (RSC), 2014
- 2014
- Engelska.
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-6848 .- 1744-683X. ; 10:16, s. 2775-2784
- Relaterad länk:
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http://dx.doi.org/10...
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https://research.cha...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Immunogenicity (i.e., the ability to initiate immune reactions) is one of the major challenges for the development of new drugs, as it may turn the developed drug therapeutically ineffective or cause severe immune-related effects. Using single molecule force spectroscopy, we study rupture forces between the positively charged, endogenous protein platelet factor 4 (PF4; also known as CXC chemokine ligand 4, CXCL4) and the antithrombotic drug heparin and other negatively charged glycosaminoglycans (GAGs), which are known to form immunogenic PF4/GAG-complexes (e. g., heparin and dextran sulfate) as well as non-immunogenic complexes (e. g., chondroitin sulfate A). Our measurements suggest that the average number of sulfate groups per monosaccharide unit (i.e., the degree of sulfation DS) does not affect the unbinding characteristics of single PF4/GAG-bonds (reaction coordinate x(0) = 2.2 +/- 0.2 angstrom, energy barrier Delta G approximate to -1 k(B)T). However, the average number of GAG bonds formed to a single PF4 molecule increases with increasing DS as indicated by a rising frequency of unbinding events, suggesting a multivalent binding scheme between PF4 and GAGs. Our studies show that at least three GAG bonds have to be formed to each PF4 molecule to induce epitope formation on the PF4/GAG-complex to which PF4/GAG-complex specific antibodies bind. Hence, GAG-based drugs that form less than three bonds per PF4 molecule are unlikely to constitute PF4/drug-complexes that are of immunologic relevance.
Ämnesord
- NATURVETENSKAP -- Fysik (hsv//swe)
- NATURAL SCIENCES -- Physical Sciences (hsv//eng)
- NATURVETENSKAP -- Fysik -- Den kondenserade materiens fysik (hsv//swe)
- NATURAL SCIENCES -- Physical Sciences -- Condensed Matter Physics (hsv//eng)
Nyckelord
- CANTILEVERS
- P1246
- ONG BH
- V2
- V73
- HEPARIN-INDUCED THROMBOCYTOPENIA
- ONG BH
- ANTIBODIES
- 1982
- BRITISH JOURNAL OF HAEMATOLOGY
- 1989
- POLYSACCHARIDES
- BINDING-SITES
- MICROSCOPE
- LANCET
- CALIBRATION
- PLATELET FACTOR-IV
- P235
- SPRING CONSTANT
- COMPLEX
- IMMUNOGENICITY
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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