Pepti-drift: Toxicity-Repulsive Drifting for Antigen-Conditioned Discrete Peptide Generation

Peptides are a promising therapeutic modality that combine the chemical tunability of small molecules with the target specificity of macromolecular therapeutics.

However, designing antigen-specific binding peptides while avoiding toxicity remains a major challenge for therapeutic peptide discovery.

Here, we present Pepti-drift, a toxicity-aware latent refinement framework that generates peptide candidates through a single antigen-conditioned drift step.

In a peptide embedding space, Pepti-drift learns to attract generated peptide latents toward antigen-matched binding peptides while repelling them from toxicity-associated regions.

This is challenging because binding-promoting physicochemical features often overlap with toxicity-associated features in peptide representation space.

To address this, we introduce a warm-up strategy to stabilize this competing objective by first learning binding-oriented attraction and then increasing toxicity repulsion.