Investigation of mechanism-based inhibitors of complement targeting the activated thioester of human C3

Biochemical Pharmacology
A Sahu, M K Pangburn

Abstract

An intramolecular thioester bond in complement protein C3 is vital for covalent attachment of C3b (the proteolytically activated form of C3) to biological surfaces and for activation of the complement system. Proteolytic removal of C3a from C3 activates the thioester in the C3b fragment. Activated C3b primarily forms ester bonds with hydroxyl groups of carbohydrates on complement activating surfaces, but it has also been shown to react with the hydroxyl group of tyrosine and with specific Ser and Thr residues on IgG and on complement protein C4b. To examine the reactivity of the thioester, several families of hydroxylated compounds were examined. Reactivity of a series of substituted phenols varied over two orders of magnitude and demonstrated a linear correlation between reactivity and the Hammett substituent constants. Hydroxylated drugs including members of the L-DOPA/epinephrine family and hydroxamic acids also were examined. Compounds were identified that were 20,000 times more reactive than carbohydrates. These compounds were found to inhibit both the classical and alternative pathways of complement activation. Although the specificity of the thioester for its natural biological targets appears to be determined by many st...Continue Reading

References

Jun 1, 1992·Brain Research. Molecular Brain Research·D G Walker, P L McGeer
Sep 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·M C CarrollD E Isenman
Feb 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·M H de Bruijn, G H Fey
Jun 1, 1987·The Journal of Experimental Medicine·Y TakataK Inoue
Jan 1, 1984·Springer Seminars in Immunopathology·M K Pangburn, H J Müller-Eberhard
Oct 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·B F TackJ W Prahl
Jan 1, 1981·The Biochemical Journal·R B SimE Sim
Aug 1, 1994·The American Journal of Psychiatry·P S Aisen, K L Davis
Jan 1, 1994·Alzheimer Disease and Associated Disorders·P L McGeerE G McGeer
Feb 1, 1994·Immunology Today·U HolmskovJ C Jensenius
Apr 1, 1994·Cardiovascular Research·K S KilgoreB R Lucchesi

❮ Previous
Next ❯

Citations

Feb 1, 1997·Protein Science : a Publication of the Protein Society·S K Law, A W Dodds
Apr 16, 1998·Protein Science : a Publication of the Protein Society·D MorikisJ D Lambris
Jul 3, 2008·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Clark D West, John J Bissler
Jun 3, 1999·Biochemical Pharmacology·A SahuM K Pangburn
Mar 4, 2000·Molecular Immunology·F VivancoC Pastor
Jul 25, 2000·Immunopharmacology·A Sahu, J D Lambris
Apr 11, 2007·Current Opinion in Nephrology and Hypertension·Patrick D Walker
Dec 8, 2000·ASAIO Journal : a Peer-reviewed Journal of the American Society for Artificial Internal Organs·J Janatova
Jun 17, 2006·Circulation Research·J MoccoE Sander Connolly
Dec 7, 2007·Bioorganicheskaia khimiia·L V KozlovA P Kaplun
May 21, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Archana P Kadam, Arvind Sahu
Aug 7, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Athena M SoulikaJohn D Lambris
Aug 18, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·A SahuJ D Lambris
Nov 25, 2017·Journal of Veterinary Internal Medicine·D M HernandezE Behling-Kelly
Jul 12, 2001·The Journal of Biological Chemistry·L VidarteF Vivanco

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alternative Complement Pathway

The Alternative Complement Pathway is part of the innate immune system, and activation generates membrane attack complexes that kill pathogenic cells. Discover the latest research on the Alternative Complement Pathway.