De novo design of peptide binders to conformationally diverse targets with contrastive language modeling.
Designing binders to target undruggable proteins presents a formidable challenge in drug discovery. In this work, we provide an algorithmic framework to design short, target-binding linear peptides, requiring only the amino acid sequence of the target protein. To do this, we propose a process to generate naturalistic peptide candidates through Gaussian perturbation of the peptidic latent space of the ESM-2 protein language model and subsequently screen these novel sequences for target-selective interaction activity via a contrastive language-image pretraining (CLIP)-based contrastive learning architecture. By integrating these generative and discriminative steps, we create a Peptide Prioritization via CLIP (PepPrCLIP) pipeline and validate highly ranked, target-specific peptides experimentally, both as inhibitory peptides and as fusions to E3 ubiquitin ligase domains. PepPrCLIP-derived constructs demonstrate functionally potent binding and degradation of conformationally diverse, disease-driving targets in vitro. In total, PepPrCLIP empowers the modulation of previously inaccessible proteins without reliance on stable and ordered tertiary structures.
Duke Scholars
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Related Subject Headings
- Protein Conformation
- Protein Binding
- Peptides
- Models, Molecular
- Humans
- Drug Discovery
- Drug Design
- Amino Acid Sequence
- Algorithms
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Protein Conformation
- Protein Binding
- Peptides
- Models, Molecular
- Humans
- Drug Discovery
- Drug Design
- Amino Acid Sequence
- Algorithms