PubMed · 10857106
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A Väkevä, S Meri. 2000. Complement deposition in tissues.. https://doi.org/10.1385/1-59259-056-x%3A113
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C3 convertase is a key enzyme in the complement cascade and is an attractive therapeutic target for drug design. Recent studies have demonstrated that this enzyme is inhibited by compstatin (Morikis, D. , Assa-Munt, N., Sahu, A., Lambris, J.D., 1998. Solution structure of Compstatin, a potent complement inhibitor. Protein Sci. (7) 619-627; Sahu, A., Kay, B.K., Lambris, J.D., 1996. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J. Immunol. (157) 884-891), a 13 amino acid cyclic peptide that binds to C3. Since the enzyme exhibits some homology to serine proteases, substrate-based design could be another avenue for drug design. In this study, we confirm the activity of compstatin using different sources of enzyme and different assay systems. We also tested the activity of substituted compstatin analogs and compared the selectivity and toxicity of these compounds to peptidyl alpha-ketoheterocyclic compounds. Our work confirms the activity of compstatin in both alternative and classical complement pathways, describes 11 new active analogs of this cyclic peptide, and provides evidence for key segments of the peptide for activity. Compstatin and related active analogs showed little or no inhibition of clotting or key enzymes in the clotting cascade nor did they appear to have significant cytotoxicity. The characteristics of compstatin suggest that this peptide and its analogs could be attractive candidates for further clinical development. By contrast, known serine protease inhibitors, including peptidyl alpha-ketoheterocycles, did not inhibit C3 convertase illustrating the atypical nature of this enzyme.
Ligustrum vulgare and Phillyrea latifolia leaves were well known in the Mediterranean historical medicine for their oropharyngeal anti-inflammatory effects. At the present time a popular phytotheraputical use of these species remains only in a few isolated southern European areas. Phytochemical and phytopharmacological studies of the methanolic extractives of their leaves were carried out. Flavonoidic fractions as well as different isolates, apigenin and luteolin derivatives showed significant in vitro complement inhibiting effects on the classical pathway of the complement system. A possible phytoceutical utilisation of the aerial parts of these species could represent (especially regarding the genus Phillyrea) an interesting perspective for many semi-arid Mediterranean regions.
Fucoidans and laminarans from Laminaria cichorioides, Laminaria japonica, Fucus evanescens, laminaran from Laminaria gurjanovae, other beta-D-glucans (translam, pustulan and zymosan) and lambda-carrageenan from Chondrus armatus were used to study the effect of water-soluble polysaccharides from seaweeds on the alternative pathway of complement (APC). beta-D-Glucans and fucoidans under study differed appreciably from each other by structural characteristics, and also by degree of purification. beta-D-glucans, on ability to bind complement, ranked in a line according to a degree of their purification. Highly purified beta-D-glucans under study did not reveal an ability to bind complement. The fucoidans were divided conventionally into three groups according to their action on APC. Highly sulfated alpha-L-fucan from L. cichorioides with the greatest activity toward APC and caused 50% inhibition of reaction of activation (RA) of APC in a concentration of 0.5-0.7 mg/ml. Opposite 50% of inhibition of lysis of erythrocytes by sulfated heterogeneous fucoidan from L. japonica was achieved with 20 mg/ml. All other fucoidans and lambda-carrageenan have activity at 6-10 mg/ml concentration. Decreasing the sulfate content from 36% up to 9% in sample fucoidans under study was not reflected practically in the 50% inhibition concentration. Apparently, the degree of sulfating of fucoidans did not influence their action on APC. But the positive influence of fucose in structure of polysaccharide was obvious.