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Structure‐based design of decoy chemokines as a way to explore the pharmacological potential of glycosaminoglycans
Author(s) -
Adage Tiziana,
Piccinini AnnaMaria,
Falsone Angelika,
Trinker Martin,
Robinson James,
Gesslbauer Bernd,
Kungl Andreas J.
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02089.x
Subject(s) - decoy , glycosaminoglycan , chemokine , plasma protein binding , microbiology and biotechnology , chemistry , function (biology) , computational biology , biochemistry , biology , receptor
Glycosaminoglycans (GAGs) are a class of highly negatively charged, unbranched, O‐linked polysaccharides that are involved in many diseases. Their role as a protein‐binding matrix on cell surfaces has long been recognized, but therapeutic approaches to interfere with protein–GAG interactions have been limited due to the complex chemistry of GAGs, on one hand, and due to the lack of specific antibodies against GAGs, on the other hand. We have developed a protein engineering platform (the so‐called CellJammer ® technology), which enables us to introduce higher GAG‐binding affinity into wild‐type GAG‐binding proteins and to combine this with impaired biological, receptor‐binding function. Chemokines are among the prototypic GAG‐binding proteins and here we present selected results of our CellJammer technology applied to several of these proinflammatory proteins. An overview is given of our lead decoy protein, PA401, which is a CXCL8‐based mutant protein with increased GAG‐binding affinity and decreased CXCR1/2 binding and activation. Major results from our CCL2 and CCL5 programmes are also summarized and the potential for clinical application of these decoy proteins is presented.