Federico Bernal, Ph.D.

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.