Stapled Peptide Design Group

RESEARCH PROJECTS

Dissecting and targeting the BCL-2 family interaction network with hydrocarbon-stapled peptides

We have employed stapled peptides to investigate basic apoptotic mechanisms and develop a new class of unique apoptosis modulating agents that recapitulate BH3 and BH4 domain activities in targeting BAX and BAK. Our characterization of the differential regulatory sites on BAK and BAX has provided a blueprint for the development of selective pharmacologic agents to directly activate the death program in human cancer.

Hydrocarbon-stapled peptides to target diverse pathologic protein interactions in human cancer

Stapled peptides serve as unique chemical probes that have uncovered new insights into cancer signaling pathways. The results of our collaborative projects demonstrate the potential broad impact of stapled peptides as a platform technology that yields chemical tools and prototype therapeutics for cancer. For example, we have reported stapled peptides that target (1) EED to inhibit the PRC2 complex, (2) BCL-2 family proteins to reactivate apoptosis in resistant hematologic cancers, (3) β-catenin to block aberrant Wnt signaling, and (4) KRAS and its mutant isoforms to block pathologic nucleotide exchange activity.

Chemically-diversified stapled peptides as probes for structural, proteomic, and cellular investigations

As active members of the collaborative Linde Program in Cancer Chemical Biology at Dana-Farber, we have tailored the design, synthesis, and application of chemically-stabilized α-helical peptides to interrogate biological mechanisms of action and target protein interactions in vivo for potential therapeutic benefit. Best-practices in advancing and applying stapled peptide technology are outlined in our methodologic publications and have been adopted by over two dozen unaffiliated research groups nationally and around the world.

Stapled peptides as viral fusion inhibitors and prototype immunogens

New therapeutic strategies are needed to prevent and treat viral infections, as the threat of new viruses and widespread outbreaks is ever-present. Stapled peptides have demonstrated potential as viral fusion inhibitors in diverse infections that employ a fusogenic six-helix bundle mode of entry, such as HIV and RSV. Similarly, we have demonstrated that stapled peptides can serve as high fidelity, protease-resistant mimics of highly conserved antigenic structures recognized by the broadly neutralizing HIV-1 antibodies, 4e10 and 10e8, highlighting their potential utility as prototype immunogens for the development of an HIV-1 vaccine.