Description:
Princeton
University Invention # 09-2488
The
present invention relates to a series of novel analogues to compstatin. Based on
experimental SPR (Surface Plasmon Resonance) and IC50 binding data these new
analogues show greater binding affinity compared to native compstatin and are
therefore potentially more potent drug candidates for diseases related to
improper complement activation. Low nanomolar binding affinities similar to
alternative analogues described in the literature have been achieved and, based
upon testing modifications with non-natural amino acids, even greater C3c
binding affinities are anticipated.
Researchers
at Princeton University, Department of Chemical Engineering and University of
California, Bioengineering have developed and used two de novo protein design
frameworks to discover these new compstatin variants. The framework utilizes two
stages: a sequences selection stage and a binding affinity calculation stage.
The sequence selection stage produces a rank-ordered list of amino acid
sequences with the lowest energies based upon the template structure
(compstatin). The binding affinity calculation stage takes the sequences from
stage one and calculates approximate binding affinities for each sequence. The
sequences are then ranked according to binding affinities, elucidating sequences
that have higher predicted binding affinities than the native compstatin, making
them more potent inhibitors of C3c.
Although
complement activation is part of a normal inflammatory response, inappropriate
complement activation can cause host-cell damage, which is implicated in a
number of pathological conditions, such as autoimmune diseases, stroke, heart
attack, Alzheimer¿s disease and burn injuries.
Compstatin
has shown highly promising results in a number of clinically relevant trials.
These new compstatin analogs may offer a new second generation of complement
based therapeutics leads.
Princeton
is currently seeking commercial partners for the further development and
commercialization of this opportunity. Patent protection is pending.
References:
Bellows
ML, Fung HK, Taylor MS, Floudas CA, López de Victoria A, Morikis D, New
Compstatin Variants through Two De Novo Protein Design Frameworks,
Biophysical Journal, Vol 98, May 2010, 2337-2346
López
de Victoria A, Gorham Jr RD, Bellows ML, Ling J, Lo DD, Floudas CA, Morikis D, A
new Generation of Potent Complement Inhibitors of the Compstatin Family,
Chemical Biology & Drug Design, Vol 77, Issue 5, May 2011
Tamamis
P, Morikis D, Floudas CA, Species Specificity of the complement inhibitor
compstatin investigated by all-atom molecular dynamics simulations, Proteins:
Structure, Function, and Bioinformatics, Vol. 78, Issue 12, Sept. 2010 pg
2655-2667
For
more information on Princeton University invention # 09-2488, please contact:
Laurie
Tzodikov (609) 258-7256 tzodikov@princeton.edu