Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction
https://doi.org/10.1038/s41589-026-02237-7
École Polytechnique Fédérale de Lausanne (EPFL)
Cyclic peptides represent a promising way to target previously undruggable protein-protein interactions (PPIs). However, their low cell permeability limits their use against intracellular targets.
By using their high-throughput cyclic peptide synthesis platform, the authors generated a 15,000-member library within the membrane-permeable cyclic peptide property space. This library was then screened against the KEAP1-NRF2 PPI using a TR-FRET assay. Iterative design, build, and test rounds were used to improve potency ~1000-fold. Previous cyclic peptide inhibitors of this interaction were based on the native NRF2 sequence, which contains several acidic residues that limited their permeability. The lead peptide showed moderate activity in a cellular assay, highlighting the benefit of screening in the "membrane permeable" cyclic peptide space.
On the Scope of DCAF1-Recruiting PROTACs Degrading Protein Kinases
https://doi.org/10.1021/acs.jmedchem.6c00383
Goethe University Frankfurt, NEOsphere Biotechnologies GmbH, Merck Healthcare KGaA
Most PROTAC drug development relies on two E3 ligases, CRBN and VHL. But there is emerging evidence that the efficacy of degradation could largely be determined by the E3 ligase used.
To address this, the authors assessed the emerging E3 ligase DCAF1. They did this by linking the DCAF1 ligand to promiscuous kinase ligands, which allowed them to evaluate the scope of kinase degradation by DCAF1.
They found that a large range of kinases were degraded, which further validates DCAF1 as an E3 ligase for PROTAC development. A side-by-side comparison with matched CRBN-recruiting PROTACs showed that the two ligases share a substantial overlap in their degradable kinome, though CRBN reached more kinases overall. Notably, neither the DCAF1 PROTACs nor the DCAF1 ligand showed any neo-substrate or molecular-glue activity, a potential selectivity advantage over thalidomide-based CRBN degraders.
Discovery of Biased Dual-Agonists of Glucagon-Like Peptide 1 and Glucagon Receptors through Mutation of a Conserved Aspartate
GLP-1R agonists have become a key tool for managing type 2 diabetes and for weight loss. Agonism of other GPCRs, such as GCGR and GIPR, has also shown benefits. However, full agonism via G protein and β-arrestin pathways is thought to lead to receptor desensitisation and off-target effects.
Merck found that position 9, a conserved aspartate in the glucagon and GLP-1 sequences, is a key residue for tuning this bias. A single Asp9→Glu swap in an existing dual coagonist abolished β-arrestin recruitment at both receptors. cAMP signalling was retained and receptor internalisation reduced. Despite weaker in vitro potency, this biased coagonist matched its unbiased parent at suppressing triglyceride accumulation in hepatocytes and, in diet-induced obese mice, drove robust weight loss that outperformed semaglutide. These are among the first GLP-1R/GCGR dual agonists with a clear cAMP-over-β-arrestin bias at both receptors, offering a design template for biased polyagonists.
Confusion Without Measure: Units, Assumptions, and Best Practices in Reporting Preclinical ADME/PK Data
https://doi.org/10.1021/acs.jmedchem.6c00923
Matthew C. Robinson, PostEra Inc.
The generation of ADME and DMPK data is a key task in the drug development process. However, many different pieces of data can be measured, and there are also several ways of reporting each piece of data, which can make interpreting the results more difficult than it needs to be.
In this article, the author sets out the units, assumptions, and conventions behind common preclinical ADME/PK measurements, and offers practical suggestions for reporting them more clearly. A survey of the recent literature found more than twenty different ways of reporting microsomal stability alone, and the discussion works through in vivo PK parameters such as dose, clearance, and volume of distribution before covering in vitro metabolic stability and PK/PD. A recurring theme is that scaling factors like microsomal protein per gram of liver are assumed constants that vary between institutions, so they should always be reported alongside any scaled value. The article closes with checklists for each data type.