PepALD: Macrocyclic Peptide Generation via Autoregressive Latent Diffusion

Macrocyclic peptides are promising therapeutic candidates for intracellular targets, but their design requires simultaneous control over non-natural monomer chemistry, ring topology, membrane permeability, and target binding. Existing SMILES- or HELM-string generative models either operate in long atom-level sequence spaces or treat monomers as symbolic tokens with limited chemical grounding. We introduce PepALD, an Autoregressive Latent Diffusion (ALD) foundation model for \textit{de novo} macrocyclic peptide generation. The model represents HELM monomers with structured chemical embeddings, generates each residue through context-conditioned diffusion in chemically informed latent space, predicts R-group-aware ring closures during autoregressive generation, and aligns the denoiser to affinity rewards using winner-protected diffusion-adapted preference optimization. In silico experiments demonstrate PepALD's generation quality and reward-optimization performance against representative peptide generation baselines.

Source: arXiv:2606.14510v1 - http://arxiv.org/abs/2606.14510v1 PDF: https://arxiv.org/pdf/2606.14510v1 Original Link: http://arxiv.org/abs/2606.14510v1