Aptamer-derived peptide inhibitors of Rho guanine nucleotide exchange factors

Small G proteins of the Rho family and their activators the guanine nucleotide exchange factors (RhoGEFs) regulate essential cellular functions and their deregulation has been associated with an amazing variety of human disorders, including cancer, inflammation, vascular diseases, and mental retardation. Rho GTPases and RhoGEFs therefore represent important targets for inhibition, not only in basic research but also for therapeutic purposes, and strategies to inhibit their function are actively being sought. Our lab has been very active in this field and has used the peptide aptamer technology to develop the first RhoGEF inhibitor, using the RhoGEF Trio as a model. Trio function has been described mainly in cell motility and axon growth in the nervous system via Rac1 GTPase activation, but recent findings suggest it to play also a role in the aggressive phenotype of various cancers, making it an attractive target for drug discovery. The object of this chapter is to demonstrate that targeting a RhoGEF using the peptide aptamer technology represents a valid and efficient approach to inhibit cellular processes in which Rho GTPase activity is upregulated. This is illustrated here by the first description of a peptide inhibitor of the oncogenic RhoGEF Tgat, TRIP(E32G), which is functional in vivo. On a long-term perspective, these peptide inhibitors can also serve as therapeutic tools or as guides for the discovery of small-molecule drugs, using an aptamer displacement screen.