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Improvement of the anti-C3 activity of compstatin using rational and combinatorial approaches
D Morikis1, A M Soulika, B Mallik
1Department of Chemical and Environmental Engineering, University of California at Riverside, Riverside, CA 92521, USA. dmorikis@engr.ucr.edu
Insights
Compstatin analogues were designed using structural and computational methods, yielding a 16-fold more active peptide. Molecular dynamics simulations revealed dynamic properties crucial for future analogue design.
Area of Science:
- Immunology
- Structural Biology
- Computational Chemistry
Background:
- Compstatin is a cyclic peptide inhibiting C3 cleavage, a key step in the complement cascade.
- C3 cleavage generates pro-inflammatory C3a, opsonin C3b, and the membrane attack complex.
Purpose of the Study:
- To design more potent compstatin analogues through rational and combinatorial approaches.
- To understand the dynamic behavior of compstatin for improved analogue design.
Main Methods:
- Rational design based on compstatin's 3D structure.
- Experimental and theoretical combinatorial design using phage display and computational optimization.
- Molecular dynamics simulations to study compstatin's dynamic character.
Main Results:
- Developed compstatin analogues with significantly improved activity.
- Identified a lead analogue 16-fold more active than the parent peptide.
- Revealed an ensemble of interconverting conformers for compstatin.
Conclusions:
- Structural and computational strategies are effective for designing potent compstatin analogues.
- Understanding compstatin dynamics is essential for future structure-activity and dynamics-activity relationship-based designs.
Abstract:
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-NH(2) (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.
