Compstatin is a 13-residue cyclic peptide that has the ability to inhibit the cleavage of C3 to C3a and C3b. The effects of targeting C3 cleavage are threefold, and result in hindrance of: (i) the generation of the pro-inflammatory peptide C3a, (ii) the generation of opsonin C3b (or its fragment C3d), and (iii) further complement activation of the common pathway (beyond C3) with the end result of the generation of the membrane attack complex. We will report on our progress on: (i) rational design of more active compstatin analogues based on the three-dimensional structure of compstatin, (ii) experimental combinatorial design based on the generation of a phage-displayed peptide library partially randomized with the implementation of structure-induced restraints, and (iii) theoretical combinatorial design based on a novel computational optimization method, structure-induced restraints and flexible structural templates. All three approaches have resulted in analogues with improved activities. Currently, the lead analogue has the sequence acetyl-I[CVYQDWGAHRC]T-NH2 (where the brackets denote cyclization), and is 16-fold more active than the parent peptide. We will also report on our progress towards understanding the dynamic character of compstatin using molecular dynamics simulations. The identification of an ensemble of interconverting conformers of compstatin with variable populations is a first step towards the incorporation of dynamic elements in the design of new analogues using dynamics–activity relationships in addition to structure–activity relationships.
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Conference Article|
February 01 2004
Improvement of the anti-C3 activity of compstatin using rational and combinatorial approaches
D. Morikis;
D. Morikis
1
*Department of Chemical and Environmental Engineering, University of California at Riverside, Riverside, CA 92521, U.S.A.
1To whom correspondence should be addressed (e-mail dmorikis@engr.ucr.edu or lambris@mail.med.upenn.edu).
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A.M. Soulika;
A.M. Soulika
†Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar-Chance Laboratories, Philadelphia, PA 19104, U.S.A.
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B. Mallik;
B. Mallik
*Department of Chemical and Environmental Engineering, University of California at Riverside, Riverside, CA 92521, U.S.A.
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J.L. Klepeis;
J.L. Klepeis
‡Department of Chemical Engineering, Princeton University, Princeton, NJ 08544, U.S.A.
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C.A. Floudas;
C.A. Floudas
‡Department of Chemical Engineering, Princeton University, Princeton, NJ 08544, U.S.A.
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J.D. Lambris
J.D. Lambris
1
†Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar-Chance Laboratories, Philadelphia, PA 19104, U.S.A.
1To whom correspondence should be addressed (e-mail dmorikis@engr.ucr.edu or lambris@mail.med.upenn.edu).
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 Biochemical Society
2004
Biochem Soc Trans (2004) 32 (1): 28–32.
Citation
D. Morikis, A.M. Soulika, B. Mallik, J.L. Klepeis, C.A. Floudas, J.D. Lambris; Improvement of the anti-C3 activity of compstatin using rational and combinatorial approaches. Biochem Soc Trans 1 February 2004; 32 (1): 28–32. doi: https://doi.org/10.1042/bst0320028
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