Development of C5a receptor antagonists. Differential loss of functional responses
| Autor: | Z D Konteatis, S J Siciliano, G Van Riper, C J Molineaux, S Pandya, P Fischer, H Rosen, R A Mumford, M S Springer |
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| Rok vydání: | 1994 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 153:4200-4205 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.153.9.4200 |
| Popis: | C5a is a 74-amino acid glycoprotein generated on activation of the C system. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antagonist would be of considerable therapeutic importance. However, efforts at generating antagonists have so far been unsuccessful. Structure/activity studies of the C terminus of C5a have generated peptide analogues with nanomolar affinities, but all of these retain strong agonist properties. We now report hexapeptides of the form NMePhe-Lys-Pro-dCha-X-dArg in which increasing aromaticity at position 5 leads to a progressive loss of agonism with little change in binding affinity. The different responses induced by C5a are lost in the order: degranulation before Ca(2+)-flux before chemotaxis. We also describe the first full antagonist of C5a, because the peptide in which x = Trp is not only devoid of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated G protein activation. |
| Databáze: | OpenAIRE |
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