We developed NestLink, an innovative technological concept that combines the benefits of screens and selections (Egloff et al. , Nature Methods, 2019). At the heart of our technology stand the so called flycodes – genetically encoded peptide barcodes designed for optimal detection by mass spectrometry (LC-MS). Through a combination of state-of-the-art LC-MS and next generation sequencing, we process thousands of library members as an ensemble, while still allowing for characterization of individual candidate molecules within the processed pool of proteins. Hence, we invented a novel protein selection principle that operates in the absence of a classical genotype-phenotype linkage (Patent WO2018078167A1). This paradigm-shift enables novel protein engineering applications, which operate independently of large display particles such as phages and ribosomes.
The flycode technology facilitates identification of binders against integral membrane proteins embedded in living cells with high efficiency. Further, we characterized thousands of off-rates in vitro at once and deep-mined camelid immune repertoires for target-binding nanobodies. Current projects explore the application of flycodes in vivo, with the aim to reduce the number of animal trials required for biomolecular drug development.
As translational projects with a direct link to bacterial pathogens, we currently use the flycode technology to generate nanobodies and sybodies as pathogen capture reagents for rapid diagnostics of blood stream infections (project funded by the NRP 72 “Antimicrobial Resistance”). In collaboration with Sebastian Hiller (Biozentrum, Basel), we deep-mine large pools of nanobodies and sybodies for binders that recognize the essential outer membrane protein BamA with the aim to develop novel antibiotics against multidrug-resistant gram-negative pathogens (funded by a SNF BRIDGE grant).