In this presentation, I will discuss two ongoing projects in our lab that exemplify our approach to peptide science at the interface of chemical biology and synthetic biology.
The first project involves the interrogation of self-assembling proteins that form bacterial organelles. Relatively little is known about the molecular fundamentals of protein-based organelles, especially the parameters that govern how essential substrates diffuse through their pores. I will outline our systematic analysis of 24 designed mutants based on the T. maritima encapsulin protein organelle, each featuring pores of different size and charge.1,2 We combine cryo-EM, molecular dynamics, and stopped flow kinetics with a peptide sensor, to uncover the complex interplay of factors that determines the biophysical properties of these organelles.
The second project involves the development of cyclic peptide probes for protein targets in ‘ALT-positive’ cancers which leverage a non-canonical pathway to maintain telomere length and replicate indefinitely. I will detail the discovery of peptide inhibitors with nanomolar affinity that disrupt FANCM-BTR,3,4 a key protein-protein interaction that regulates the proliferation of ALT-positive cancers, along with promising results from cellular assays on selected hits.