Peptide inhibitors of C3 breakdown

• Published in: Clinical and experimental immunology Vol. 79; no. 3; pp. 454 - 458
• Main Authors: PEAKE, P., SZELKE, M., JONES, D. M., SINGLETON, A., SUEIRAS‐DIAZ, J., LACHMANN, P. J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.1990; Blackwell
• Subjects: Biological and medical sciences; Complement; Complement Activating Enzymes - antagonists & inhibitors; Complement C3 - metabolism; Complement C3-C5 Convertases - antagonists & inhibitors; Complement C3b Inactivator Proteins - physiology; Complement Factor H; Fundamental and applied biological sciences. Psychology; Fundamental immunology; inhibitors; Molecular immunology; Oligopeptides - pharmacology; peplides; Peptides; Alternative pathway complement; Complement C3; Transition state; Enzyme inhibitor; Substrate analog; Peptidic synthesis
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.1990.tb08111.x

SUMMARY We have investigated the development of substrate‐based inhibitors of complement enzymes. Sequences around the scissile Arg77‐Ser78 bond of C3 have been synthesized and tested as inhibitors of C3 convertase. The best inhibition was found with the tetrapeptide Ac‐Arg‐Ser‐Asn‐Leu‐OH (H‐576); extending this sequence in cither direction reduced inhibitory activity. Preliminary experiments with peptides in which the scissile bond —CO—NH— was replaced with non‐hydrolysable moieties such as— CO—CH2— (H‐497) and —CH2—NH— (H‐336) failed to show enhanced inhibition. One of the longer chain inhibitors H‐416 containing DArg77‐Ser78 was unexpectedly found to potentiate iC3 cleavage by factors I and H but did not inhibit the intact alternative pathway. The same peptide also bound to factor H. Tt is concluded that the binding requirements of the C3 convertase are more sophisticated than can be satisfactorily imitated simply by linear sequences around the scissile bond of C3.