Design-Rules for Stapled Alpha-Helical Peptides with On-Target In Vivo Activity: Application toMdm2/X dual antagonists
Chandramohan, A.; Josien, H.; Yuen, T.; Duggal, R.; Spiegelberg, D.; Yan, L.; Juang, Y. C. A.; Ge, L.; Aronica, P.; Kaan, H. Y. K.; Lim, Y. H.; Peier, A.; Sherborne, B.; Hochman, J.; Lin, S.; Biswas, K.; Henry, B.; Nestor, M.; Verma, C. S.; Lane, D. P.; Sawyer, T. K.; Garbaccio, R.; Kannan, S.; Brown, C. J.; Johannes, C. W.; Partridge, A. W.
Show abstract
Stapled -helical peptides can bind to and modulate historically intractable targets while addressing the traditional liabilities associated with peptide therapeutics. However, their pipeline advancement has been impeded by the challenges of identifying peptides with sufficient cellular uptake to engage the target protein while lacking off-target toxicities. Here, we advance the field to arrive at a workflow for identifying advanced stapled peptide lead molecules with on-target in vivo activity with no off-target cell proliferation effects. Specifically, we generated a >350-member library based on ATSP-7041, a stapled peptide Mdm2(X) antagonist with validated on-target cellular effects but with significant off-target activity. Key insights from library analysis include 1) a clear correlation between lipophilicity and permeability, 2) removal of positive charge to avoid off-target toxicities, 3) judicious placement of anionic residues to enhance peptide solubility/behavior, 4) optimization of C-terminal length and helicity to enhance cell activity, 5) optimization of staple type/number to avoid polypharmacology. Incorporation of one or more of these attributes led to molecules with improved in vitro and in vivo activities (up to a >292x improved cell proliferation EC50). A subset of peptides were devoid of off-target cell proliferation effects in cell lines lacking wild-type p53 protein (up to a >3800x on-target index). This latter improvement contrasted with clinical Mdm2 antagonistic molecules. Application of these design rules to a distinct Mdm2(X) peptide series resulted in rapid improvement in cellular activity (>150x) and removal of off-target toxicities. Overall, the detailed workflow outlined here should help researchers identify stapled -helical peptides for therapeutic impact.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Discovery of CD28-Targeted Small Molecule Inhibitors of T Cell Co-stimulation Using Affinity Selection-Mass Spectrometry (AS-MS) and Ex Vivo Validation 94%
- Development of potent and selective CK1α Molecular Glue Degraders 94%
- A Lipid Prodrug Strategy Enhances Targeted Protein Degrader CNS Pharmacokinetics 94%
Similar papers in this journal
- AI-Assisted Discovery and Optimization of Small Molecule TREM2 Agonists with Functional Microglial Activity 94%
- Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2 93%
- Fragment Screening and Structure-Guided Development of Heparanase Inhibitors Reveals Orthosteric and Allosteric Inhibition 93%
Similar papers in this journal
- AI-Guided Design of Cyclic Peptide Binders Targeting TREM2 Using CycleRFdiffusion and Experimental Validation 95%
- Design and Biophysical Characterization of Second-Generation Cyclic Peptide LAG-3 Inhibitors for Cancer Immunotherapy 95%
- Design and Validation of the First-in-Class PROTACs for Targeted Degradation of the Immune Checkpoint LAG-3 94%
Similar papers in this journal
- Overcoming Immune Checkpoint Inhibitor Resistance via Potent and Selective Dual αvβ6/8 Inhibitors Based on Engineered Lasso Peptides 94%
- Modulation of the 14-3-3σ/C-RAF autoinhibited complexby molecular glues 94%
- A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.