Federico Bernal, Ph.D.
The Bernal Group has pioneered the use of hydrocarbon stapled alpha-helical peptides to study protein-protein and protein-DNA interactions. This powerful methodology has resulted in the development of compounds to regulate cancer pathogenesis pathways, including the p53 network and the linear chain ubiquitin assembly complex (LUBAC). Further work in the stapled peptide arena has led to the development of inhibitors of bacterial transcription factors involved virulence and pathogenicity as well as compounds targeting the molecular machinery involved in viral infectivity.
The development of therapeutics has evolved significantly over the course of the last two decades with significant efforts geared towards the identification of treatments that selectively target a specific signaling pathway while bearing minimal off-target effects. Protein-protein interactions ultimately govern the vast majority of cellular functions, and an understanding of the molecular interactions occurring within multiprotein complexes is critical for the design and production of inhibitors targeting a specific pathway. The assembly of protein complexes relies heavily on a pre-determined three-dimensional arrangement of atoms; and, in many instances, the interactions take place across extended surfaces devoid of binding pockets, making them inaccessible to small molecules.
Our lab makes use of stapled peptides to target interactions mediated by alpha-helical interfaces. Stapled peptides are hydrocarbon-constrained alpha helices which have emerged as a class of molecular probes and therapeutices capable of targeting molecular pathways with a high degree of selectivity both in vitro and in vivo. Given their ease of synthesis and their drug-like properties, our group has focused on targeting signaling systems ranging from protein-protein interactions relevant in cancer such as the linear ubiquitin assembly chain complex (LUBAC). More recently we have shifted our focus to develop compounds that target protein-DNA interaction, and this foray has led us to the study of transcription factor interactions in bacterial and eukaryotic systems. We have embarked on a study of the bacterial transcription factor sigma-54, which is responsible for the pathogenicity of several disease-causing bacteria, and we are currently testing compounds that target the interaction between sigma-54 and its promoters. Finally, we have expanded our reach by targeting molecular machines involved in the viral infection process, and to this end, we are developing inhibitors against filoviruses and flaviviruses in collaboration with the NIAID Integrated Research Facility.
Selected Recent Publications
Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms.Cancer Discov. 4: 480-93, 2014. [ Journal Article ]
- Am J Cancer Res. 2: 492-507, 2012. [ Journal Article ]
- Nat Med. 18: 1239-1247, 2012. [ Journal Article ]
- Cancer Cell. 18: 411-422, 2010. [ Journal Article ]
- Methods Enzymol. 446: 387-408, 2008. [ Journal Article ]
Dr. Bernal did his undergraduate training at the Massachusetts Institute of Technology graduating in 1997 with degrees in chemistry and chemical engineering. He obtained his Ph.D. from The Scripps Research Institute in 2002 after performing work on the development of synthetic methodologies for the construction of complex marine natural products in the laboratory of K. C. Nicolaou. Dr. Bernal then returned to Cambridge, MA to undergo postdoctoral training in chemical biology at Harvard University in the group of Gregory L. Verdine. He then continued his foray into cancer chemical biology in the laboratory of Loren D. Walensky at the Dana-Farber Cancer Institute. He established his laboratory in the Metabolism Branch (now the Lymphoid Malignancies Branch) of the Center for Cancer Research at NCI in 2010 and subsequently moved in 2014 to the Laboratory of Protein Dynamics and Signaling in Frederick, MD. His research focus involves the investigation and manipulation of disease pathways with synthetic molecules.
|Francisco Aguilar Alonso Ph.D.||Postdoctoral Fellow (Visiting)|