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Design and NMR Characterization of Active Analogues of Compstatin Containing Non-Natural Amino Acids

We present new findings in our drug discovery effort to develop an anticomplement therapeutic. We have designed several active analogues of compstatin by altering its amino acid composition at positions 4 and 9. The most effective analogues have tryptophan or fused-ring non-natural amino acids at po...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-01, Vol.48 (1), p.274-286
Main Authors: Mallik, Buddhadeb, Katragadda, Madan, Spruce, Lynn A, Carafides, Caterina, Tsokos, Christos G, Morikis, Dimitrios, Lambris, John D
Format: Article
Language:English
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Summary:We present new findings in our drug discovery effort to develop an anticomplement therapeutic. We have designed several active analogues of compstatin by altering its amino acid composition at positions 4 and 9. The most effective analogues have tryptophan or fused-ring non-natural amino acids at position 4 and alanine or an unbranched single-methyl amino acid at position 9. Twenty-one of these analogues have 2−99-fold higher activities compared to the parent peptide compstatin. The analogue Ac-V4(2Nal)/H9A-NH2 has the highest inhibitory activity with IC50 500 nM. NMR data, through NOE and chemical shift analysis, suggest the presence of interconverting conformers spanning the extended and helical regions of the Ramachandran plot, and they detect a predominant averaged conformer with coil structure and at least one flexible β-turn, of type I. The fused-ring non-natural amino acids at position 4 contribute to the formation of the hydrophobic cluster of compstatin, which has been previously proposed, together with the β-turn and a disulfide bridge, to be essential for binding to the target of compstatin, complement component C3. We propose that additional mechanisms may contribute to the structural stability of the analogues and to binding to C3, involving intra- and intermolecular electrostatic interactions of the π-electron system of side chain aromatic rings. The presence of π−π interactions for Trp4−Trp7 was confirmed with a molecular dynamics simulation for the most active analogue with natural amino acids, Ac-V4W/H9A-NH2. Alanine or aminobutyric acid at position 9 contribute to the weak propensity for helical structure of the residue segment 4−10 of the analogues, which may also play a role in increased activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0495531