Novel, Peptide-Based Radiopharmaceuticals for the Treatment of Various Solid Tumors
Ratmir Derda
Chief Operating Officer, 48Hour Discovery
Clinical success of Lutathera® led to exponential development of peptide-based targeted radiopharmaceuticals (TRP). Rapid clearance and tissue distribution of peptide and macrocycle scaffolds offer advantageous pharmacokinetic properties for TRP development making them a privilege modality for development of next generation TRPs. Genetically-encoded libraries (GEL) and DNA-encoded libraries (DEL) are standard tools that guide discovery of macrocyclic ligands
and drug leads; these technologies serve as promising starting point for design of next generation peptide-TRP. Phage display—the platform that inspired modern GEL and DEL—is one of a few technologies that permit discovery of molecular interactions in a complex milieu on the surface of cells and inside living organisms. Injection of phage libraries inside living animals and humans, known as “in vivo phage display” has been practiced using canonical peptide and
antibody libraries made of 20 natural amino acids. We bridge the power of GEL/DEL with organic synthesis to yield new classes of encoded libraries displayed on phage virion. “Late stage” modification of these GE libraries in water can routinely convert million to billion diverse starting materials to products that contain desired architectures for development of TRPs.
Alternatively, nascent phage virions bearing DNA barcodes can be used as prospectively-tagged support for synthesis of any structures. The resulting libraries, when displayed on phage are also amenable to in vivo display: they can be injected into living animals to identify the compounds that exhibit desired molecular recognition properties (e.g., interact with specific cell or organ) and pave the route for target agnostic discovery of next generation TRPs.
1. Arunika Ekanayake, et al., “Genetically Encoded Fragment-Based Discovery (GE-FBD) from Phage-Displayed Macrocyclic Libraries with Genetically-Encoded Unnatural Pharmacophores“ J. Am. Chem. Soc., 2021, 143, 14, 5497.
2. Mirat Sojitra, et al., “Genetically encoded multivalent liquid glycan array displayed on M13 bacteriophage“, Nat. Chem. Biol. 2021, 17, 806.
3. Chih-Lan Lin, et al. “Chemoenzymatic Synthesis of Genetically-Encoded Multivalent Liquid N-glycan Arrays“, BioRxiv 2022 DOI https://doi.org/10.1101/2022.08.05.503005
Ratmir Derda received his undergraduate degree in Physics from Moscow Institute of Physics and Technology in 2001, Ph.D. in Chemistry from the University of Wisconsin-Madison in 2008, under the supervision of Laura Kiessling, and postdoctoral training at Harvard University under the supervision of George Whitesides and Donald Ingber. He joined University of Alberta in 2011 as an Assistant Professor in Chemistry and was promoted to Associate and then full Professor in 2017 and 2021. In 2017 he founded 48HourDiscovery INC to translate genetically-encoded libraries and other technologies developed in Derda Group. His notable awards include X-Chem Research Excellence Award (2022); Melanie O'Neill Young Investigator Award in Biological Chemistry (2018), David Gin New Investigator Award in carbohydrate chemistry from American Chemical Society (2017), Rising Star in Chemical Biology from the International Chemical Biology Society (2016); Young Investigator Award from the Boulder Peptide Society (2014); Gold Medal at the XXIX International Chemistry Olympiad (1997).