ABSTRACT
PROteolysis TArgeting Chimeras (PROTACs) are of significant current interest for the development of probe molecules and drug leads. However, they suffer from certain limitations. PROTACs are rule-breaking molecules with sub-optimal cellular permeability, solubility, and other drug-like properties. In particular, they exhibit an unusual dose-response curve where high concentrations of the bivalent molecule inhibit degradation activity, a phenomenon known as the hook effect. This will likely complicate their use in vivo. In this study, we explore a novel approach to create PROTACs that do not exhibit a hook effect. This is achieved by equipping the target protein and E3 ubiquitin ligase ligands with functionalities that undergo rapid and reversible covalent assembly in cellulo. We report the development of Self-Assembled Proteolysis Targeting Chimeras that mediate the degradation of the Von Hippel-Lindau E3 ubiquitin ligase and do not evince a hook effect.
Subject(s)
Proteolysis Targeting Chimera , Ubiquitin-Protein Ligases , Proteolysis , Ubiquitin-Protein Ligases/metabolism , Proteins/metabolism , LigandsABSTRACT
A high affinity Streptavidin ligand was mined from a DNA-encoded library of non-peptidic oligimers and characterized structurally.
Subject(s)
Peptoids/chemistry , Peptoids/metabolism , Streptavidin/metabolism , Ligands , Protein ConformationABSTRACT
DNA-encoded library (DEL) screening has emerged as an important method for early stage drug and probe molecule discovery. The vast majority of screens using DELs have been relatively simple binding assays. The library is incubated with a target molecule, which is almost always a protein, and the DNAs that remain associated with the target after thorough washing are amplified and deep sequenced to reveal the chemical structures of the ligands they encode. Recently however, a number of different screening formats have been introduced that demand more than simple binding. These include a format that demands hits exhibit high selectivity for target vs. off-targets, a protocol to screen for enzyme inhibitors and another to identify organocatalysts in a DEL. These and other novel assay formats are reviewed in this article. We also consider some of the most significant remaining challenges in DEL assay development.
Subject(s)
Drug Discovery/methods , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Gene Library , Ligands , Peptide Library , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Phosphotransferases/antagonists & inhibitors , Phosphotransferases/metabolism , Protein Binding/drug effectsABSTRACT
In this issue of Cell Chemical Biology, Passioura et al. (2018) report another interesting application of the powerful random non-standard peptide integrated discovery (RaPID) screening method. They identify several high-affinity macrocyclic peptides for the sodium taurocholate co-transporting polypeptide (NTCP), the protein through which hepatitis B virus (HBV) enters the cell.
