Compstatin: a complement inhibitor on its way to clinical application

Adv Exp Med Biol. 2008;632:273-92. doi: 10.1007/978-0-387-78952-1_20.

Abstract

Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Alanine / metabolism
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites
  • Clinical Trials as Topic
  • Complement C3 / antagonists & inhibitors*
  • Complement C3 / metabolism
  • Complement Inactivator Proteins / pharmacology*
  • Escherichia coli / genetics
  • Forecasting
  • Humans
  • Inhibitory Concentration 50
  • Macular Degeneration / drug therapy
  • Models, Biological
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / genetics
  • Peptides, Cyclic / pharmacology*
  • Peptides, Cyclic / therapeutic use*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary

Substances

  • Complement C3
  • Complement Inactivator Proteins
  • Peptides, Cyclic
  • compstatin
  • Alanine