"It would have taken us months or even years to synthesize and screen the 80 quadrillion possible peptide sequences that the protein design program considered," John D. Lambris, PhD, a professor in Penn's Department of Pathology & Laboratory Medicine and a co-author on the study whose laboratory had discovered Compstatin in 1996. "In the end, we came up with two analogues to Compstatin each created by altering one amino acid that performed its job even better than the original protein."

Compstatin works by blocking human complement, the immune system's passive alarm network that detects pathogens in the blood. Unfortunately, complement can also attack healthy tissue, and a variety of diseases are associated with complement gone awry, such as multiple sclerosis and hemolytic anemia. In addition, complement is thought to play a role in the destruction of cells during strokes, heart attacks, and burn injuries. The complement reaction is actually a series of interlocking cascades, or chain reactions, of biochemical events involving at least 30 proteins. Compstatin works by preventing the activation of C3, a protein that functions at the point where all the complement protein cascades intersect.

The two Compstatin analogues derived from the experiment are superior in their ability to cling to and, hence, prevent the activation of the C3 complement protein. Based on these two analogs, more Compstatin analogs have since been designed, some of which are 200 fold more active that the original Compstatin, according to Lambris. These new Compstatin analogs will be further refined and tested until ready for clinical trials.

To create templates of the desired shape for Compstatin, Dimitrios Morikis, PhD, a researcher at the Department of Chemical and Environmental Engineering of University of California, Riverside, identified the th
'"/>

Contact: Greg Lester
lesterg@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
25-Aug-2003