Recifin A, a Novel and Selective Allosteric Inhibitor of Tyrosyl-DNA Phosphodiesterase I with a Unique Disulfide-bond Topology
Christina Schroeder
Senior Fellow, Genentech
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a molecular target for the sensitization of cancer cells to the FDA-approved topoisomerase inhibitors topotecan and irinotecan. However, current TDP1 inhibitors have low binding affinity or are substrate mimics with low specificity. Through high-throughput screening of natural products and extracts library in the search for novel TDP1 inhibitors, we identified a new class of complex knotted peptides with a unique disulfide-bond topology from the marine sponge Axinella sp.(1) The active component was a 42-residue peptide named recifin A. Unlike previously described TDP1 inhibitors which bind to the C-terminal catalytic domain of TDP1, recifin A acts as an allosteric inhibitor and binds to the N-terminal regulatory domain. The three-dimensional NMR structure revealed a novel fold comprising a four-strand antiparallel -sheet and two helical turns stabilized by a complex disulfide-bond network that creates an embedded ring around one of the strands. The structure is locked in place by a centrally located tyrosine residue, resulting in the Tyr-lock family name. Recifin A represents both the first of a unique structural class of knotted disulfide-rich peptides and defines a previously unseen mechanism of TDP1 inhibition that could lead to the development of a new class of TDP1 inhibitors with improved specificity that could be exploited for potential anticancer applications. .
(1) Krumpe, L.R.H. et al., JACS, 2020, 142, 21178-21188
Dr Schroeder holds a MSc. in Chemistry from University of Kalmar, Sweden, a Ph.D. in Pharmacology from the University of Queensland, Australia, and a Graduate Certificate in Research Management from Southern Cross University, Australia. She has carried out postdoctoral training at The Scripps Research Institute, USA, the University of Queensland, and the University of New South Wales, Australia. She started her independent career in 2014 at the University of Queensland’s Institute for Molecular Bioscience focusing her research on biodiscovery and peptide engineering of venom-derived bioactive peptides for the development of novel peptide-based drug leads for diseases including pain and cancer and was promoted to Associate Professor in 2020. In 2020 she moved her research to the National Cancer Institute’s Chemical Biology Laboratory, Frederick, MD, taking up a position as a Stadtman Fellow, keeping her ties with the University of Queensland as an adjunct Associate Professor position. She recently joined the Peptide Therapeutics department at Genentech as a Senior Fellow.