A US Food and Drug Administration (FDA) advisory panel has voted to loosen restrictions on controversial peptides that have become popular online, but have not been well researched for human usage. The panel narrowly voted to allow specialised pharmacies to produce drugs including BPC-157, TB-500 and KPV, a major regulatory hurdle towards making them available via prescription. Peptides are small proteins that our bodies normally produce and that have long been used to treat medical conditions, including diabetes. But unregulated injectable peptides have exploded in the online wellness community - including among many young influencers - since GLP-1s (weight loss drugs) became mainstream. The FDA does not have to follow the panel's recommendations, but often does.

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The FDA could decide whether to loosen rules around peptide production this week. Some telehealth players are already seeing dollar signs. Has anyone tried to sell you peptides yet? Once a niche interest among bodybuilders and biohackers, peptides are an increasingly popular class of substance hyped by both fringe influencers and the current US Secretary of Health and Human Services. Earlier this year, Robert F. Kennedy Jr. told the podcaster Joe Rogan that the government intended to loosen restrictions on peptide production.

Protein-protein interactions (PPIs) are governed by surface complementarity and hydrophobic interactions at protein interfaces. However, designing diverse and physically realistic protein structure and surfaces that precisely complement target receptors remains a significant challenge in computational protein design. In this work, we introduce PepBridge, a novel framework for the joint design of protein surface and structure that seamlessly integrates receptor surface geometry and biochemical properties. Starting with a receptor surface represented as a 3D point cloud, PepBridge generates complete protein structures through a multi-step process. First, it employs denoising diffusion bridge models (DDBMs) to map receptor surfaces to ligand surfaces. Next, a multi-model diffusion model predicts the corresponding structure, while Shape-Frame Matching Networks ensure alignment between surface geometry and backbone architecture. This integrated approach facilitates surface complementarity, conformational stability, and chemical feasibility. Extensive validation across diverse protein design scenarios demonstrates PepBridge's efficacy in generating structurally viable proteins, representing a significant advancement in the joint design of top-down protein structure.

A.1 Compilation and Standardization of Datasets We compile ESCAPE from 27 peptide databases by systematically extracting experimentally validated antimicrobial peptides annotated for antibacterial, antifungal, antiparasitic, or antiviral activity. Databases exclusively focusing on a single category, such as AVPdb [1] (antiviral), are directly mapped to one of the four target classes. Additionally, we follow the methodology outlined in TransImbAMP[6], selecting non-antimicrobial peptides from UniProt [7] by applying strict exclusion criteria. Specifically, we discard sequences containing keywords such as "membrane," "toxic," "secretory," "defensive," "antibiotic," "anticancer," "antiviral," or "antifungal" to enhance the quality of the negative class. For large and hierarchically structured databases such as DBAASP[8], DRAMP[9], dbAMP (with species-level annotations)[10], and SATPdb (which lists 38 functional categories)[11], we retain all peptides with annotations that map either directly or through hierarchical or taxonomic relationships to one of our four defined antimicrobial classes (antibacterial, antifungal, antiparasitic, antiviral).

Antimicrobial peptides have emerged as promising molecules to combat antimicrobial resistance. However, fragmented datasets, inconsistent annotations, and the lack of standardized benchmarks hinder computational approaches and slow down the discovery of new candidates. To address these challenges, we present the Expanded Standardized Collection for Antimicrobial Peptide Evaluation (ESCAPE), an experimental framework integrating over 80000 peptides from 27 validated repositories. Our dataset separates antimicrobial peptides from negative sequences and incorporates their functional annotations into a biologically coherent multilabel hierarchy, capturing activities across antibacterial, antifungal, antiviral, and antiparasitic classes. Building on ESCAPE, we propose a transformer-based model that leverages sequence and structural information to predict multiple functional activities of peptides. Our method achieves up to a 2.56% relative average improvement in mean Average Precision over the second-best method adapted for this task, establishing a new state-of-the-art multilabel peptide classification. ESCAPE provides a comprehensive and reproducible evaluation framework to advance AI-driven antimicrobial peptide research.

Designing protein binders targeting specific sites, which requires to generate realistic and functional interaction patterns, is a fundamental challenge in drug discovery. Current structure-based generative models are limited in generating nterfaces with sufficient rationality and interpretability. In this paper, we propose Retrieval-Augmented Diffusion for Aligned interface(RADiAnce), a new framework that leverages known interfaces to guide the design of novel binders. By unifying retrieval and generation in a shared contrastive latent space, our model efficiently identifies relevant interfaces for a given binding site and seamlessly integrates them through a conditional latent diffusion generator, enabling crossdomain interface transfer. Extensive exeriments show that RADiAnce significantly outperforms baseline models across multiple metrics, including binding affinity and recovery of geometries and interactions. Additional experimental results validate cross-domain generalization, demonstrating that retrieving interfaces from diverse domains, such as peptides, antibodies, and protein fragments, enhances the generation performance of binders for other domains. Our work establishes a new paradigm for protein binder design that successfully bridges retrieval-based knowledge and generative AI, opening new possibilities for drug discovery.

Autoregressive (AR) models, common in sequence generation, are limited in many biological tasks like de novo peptide sequencing and protein modeling by their unidirectional nature, failing to capture crucial global bidirectional token dependencies. Non-Autoregressive (NAR) models offer holistic, bidirectional representations but face challenges with generative coherence and scalability. To transcend this, we propose a hybrid framework enhancing AR generation by dynamically integrating rich contextual information from non-autoregressive mechanisms. Our approach couples a shared input encoder with two decoders: a non-autoregressive one learning latent bidirectional biological features, and an AR decoder synthesizing the biological sequence by leveraging these bi-directional features. A novel cross-decoder attention module enables the AR decoder to iteratively query and integrate these bidirectional features, enriching its predictions. This synergy is cultivated via a tailored training strategy with importance annealing for balanced objectives and cross-decoder gradient blocking for stable, focused learning.

Cyclic peptides exhibit better binding affinity and proteolytic stability compared to their linear counterparts. However, the development of cyclic peptide design models is hindered by the scarcity of data. To address this, we introduce CPSea(Cyclic Peptide Sea), a dataset of 2.71 million cyclic peptide-receptor complexes, curated through systematic mining of the AlphaFold Database (AFDB). Our pipeline extracts compact domains from AFDB, identifies cyclization sites using the β-carbon (Cβ) distance thresholds, and applies multi-stage filtering to ensure structure fidelity and binding compatibility. Compared with experimental data of cyclic peptides, CPSea shows similar distributions in metrics on structure fidelity and wet-lab compatibility. To our knowledge, CPSea is the largest cyclic peptide-receptor dataset to date, enabling end-to-end model training for the first time.

Conformational ensembles of protein structures are immensely important both for understanding protein function and drug discovery in novel modalities such as cryptic pockets. Current techniques for sampling ensembles such as molecular dynamics (MD) are computationally inefficient, while many recent machine learning methods do not transfer to systems outside their training data. We propose JAMUN which performs MD in a smoothed, noised space of all-atom 3D conformations of molecules by utilizing the framework of walk-jump sampling. JAMUN enables ensemble generation for small peptides at rates of an order of magnitude faster than traditional molecular dynamics. The physical priors in JAMUN enables transferability to systems outside of its training data, even to peptides that are longer than those originally trained on.