Evolving drugs for evolving targets
Commonly, pore-forming proteins are expressed as soluble monomers. Each protomer contains a membrane-targeting element that often selectively engages a lipid or protein binding partner to recognize its target membrane. Subsequently they oligomerize on the surface of the bilayer and then insert into it to form a lesion.
Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many cancers; and many tumors showed a different lipid composition as compared with normal tissues. We use a directed evolution approach to evolve the nanopore to engage selectively with target cancerogenic cells. The nanopore will then kill the cell or open a doorway for therapeutic drug delivery
Mutter N, Volarić J, Szymanski W, Feringa B, Maglia, G. Reversible photo-controlled nanopore assembly. JACS. (2019) doi.org/10.1021/jacs.9b06998
Mutter N, Soskine M, Huang G, Albuquerque IS, Bernardes GJL, and Maglia G. Modular pore-forming immunotoxins with caged cytotoxicity tailored by directed evolution. ACS Chem Biol. (2018) Oct 2. doi: 10.1021/acschembio.8b00720