# PepALD: Macrocyclic Peptide Generation via Autoregressive Latent Diffusion

arXiv: https://arxiv.org/abs/2606.14510 · HTML: https://mlsanity.com/paper/2606.14510/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 9 of its 26 references that are in the map.
- First posted on arXiv 12 Jun 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 9 of 9)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Direct Preference Optimization: Your Language Model is Secretly a Reward Model](https://mlsanity.com/paper/2305.18290/) (2023)
- [Diffusion Model Alignment Using Direct Preference Optimization](https://mlsanity.com/paper/2311.12908/) (2023)
- [Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models](https://mlsanity.com/paper/1811.12823/) (2018)
- [Smaug: Fixing Failure Modes of Preference Optimisation with DPO-Positive](https://mlsanity.com/paper/2402.13228/) (2024)
- [PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion](https://mlsanity.com/paper/2412.17780/) (2024)
- [PepINVENT: Generative peptide design beyond the natural amino acids](https://mlsanity.com/paper/2409.14040/) (2024)

## Abstract (arXiv)

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 textitde 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.