Genetically Encoded Fragment-Based Discovery from Phage-Displayed Macrocyclic Libraries with Genetically Encoded Unnatural Pharmacophores
- 30 March 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 143 (14), 5497-5507
- https://doi.org/10.1021/jacs.1c01186
Abstract
Genetically encoded macrocyclic peptide libraries with unnatural pharmacophores are valuable sources for the discovery of ligands for many targets of interest. Traditionally, generation of such libraries employs “early stage” incorporation of unnatural building blocks into the chemically or translationally produced macrocycles. Here, we describe a divergent late-stage approach to such libraries starting from readily available starting material: genetically encoded libraries of peptides. A diketone linchpin 1,5-dichloropentane-2,4-dione converts peptide libraries displayed on phage to 1,3-diketone bearing macrocyclic peptides (DKMP): shelf-stable precursors for Knorr pyrazole synthesis. Ligation of diverse hydrazine derivatives onto DKMP libraries displayed on phage that carries silent DNA-barcodes yields macrocyclic libraries in which the amino acid sequence and the pharmacophore are encoded by DNA. Selection of this library against carbonic anhydrase enriched macrocycles with benzenesulfonamide pharmacophore and nanomolar Kd. The methodology described in this manuscript can graft diverse pharmacophores into many existing genetically encoded phage libraries and significantly increase the value of such libraries in molecular discoveries.Keywords
Other Versions
Funding Information
- Canada Foundation for Innovation (New Leader Opportunity)
- Natural Sciences and Engineering Research Council of Canada (NSERC) (NSERC Accelerator Supplement, RGPIN-2016-402511)
This publication has 81 references indexed in Scilit:
- ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing plateletsNature Medicine, 2013
- Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanomaNature, 2010
- A scaling normalization method for differential expression analysis of RNA-seq dataGenome Biology, 2010
- AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreadingJournal of Computational Chemistry, 2009
- The rise of fragment-based drug discoveryNature Chemistry, 2009
- Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand BindingChemical Reviews, 2008
- Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activityProceedings of the National Academy of Sciences of the United States of America, 2008
- Development of a Small Peptide Tag for Covalent Labeling of ProteinsBioconjugate Chemistry, 2007
- A Novel Strategy for In Vitro Selection of Peptide-Drug ConjugatesCell Chemical Biology, 2003
- Einwirkung von Acetessigester auf PhenylhydrazinEuropean Journal of Inorganic Chemistry, 1883