The discovery of therapeutic peptides typically involves multiple rounds of screening, extensive peptide synthesis and functional assays. To reduce the time- and cost-intensive aspects of this process, we employed an AI-assisted peptide library design strategy to ensure highly functional libraries with improved stability and folding properties. Subsequently, we used ML to guide the affinity maturation. This new workflow significantly reduced efforts in peptide synthesis, thereby accelerating the discovery of therapeutic peptides.

We recently developed deep learning (DL) methods, AFCycDesign and RFpeptides, for highly accurate structure prediction, sequence design, and de novo generation of macrocyclic peptides. These new DL tools outperform the traditional physics-based methods in their speed, accuracy, and overall success rates. In this talk, I will discuss the current status and next steps for improving these tools and applying them to diverse therapeutic targets.

Autoimmunity results from the breakdown of mechanisms controlling immune tolerance. Parvus Therapeutics has developed iron-oxide nanoparticles coated with disease-relevant peptide MHC class II (pMHCII) molecules to induce antigen-specific regulatory TR1 cell conversion and expansion. This talk will focus on the identification of disease-relevant pMHCII complexes, pMHCII production and tetramer generation, reporter TCR cell line development, and in vivo TR1 conversion in PBMC-engrafted NSG mice with pMHCII nanoparticles.

Peptide actives are gaining traction, not just for internal medicine, also for topical usage. The challenges for dermal delivery, however, puts constraints on the types of peptide solutions that can be produced so far. Pushing the boundaries with longer sequences with more diversified targets necessitates the tandem evolution of large-molecule delivery solutions. This talk will review existing solutions as well as introduce novel modalities for dermal peptide products.

This talk explores how biologic CMC (Chemistry, Manufacturing, and Controls) principles can be effectively applied to peptide production across the discovery-to-development continuum. By leveraging established frameworks from biologics, we demonstrate strategies to enhance peptide quality and regulatory readiness. Key topics include process development, analytical characterization, and quality control, emphasizing a streamlined approach to accelerate peptide therapeutics toward clinical success.

The voltage-gated potassium channel Kv1.3 is upregulated in effector memory T cells, which are key drivers of autoimmune diseases, and in microglia in the brains of patients with Alzheimer’s and Parkinson’s diseases, making Kv1.3 a target for the treatment of autoimmune and neuroinflammatory diseases. Venom-derived peptides are potent inhibitors of Kv1.3; the design and development of analogues of ShK, from a sea anemone, and HsTX1, from a scorpion—which are in clinical and preclinical development, respectively—will be described. The importance of considering peptide dynamics, even for these disulfide-rich peptides, will also be emphasized.

Highly potent and selective dual integrin inhibitors were engineered from a natural lasso peptide scaffold by a combination of epitope scanning, computational design, and directed evolution. High titer production enabled the first detailed characterization of lassotide drug-like properties, including tunable in vivo PK and efficacy. Robust and durable regression of anti-mPD-1-resistant ovarian and triple-negative breast cancer tumors in mice was observed in combination with checkpoint inhibitors.

Antibodies and protein therapeutics largely target extracellular proteins, limiting their therapeutic potential. We engineered a family of membrane translocation domains (MTDs) by modifying loop sequences of a human fibronectin Type III domain. One variant, MTD4, is highly cell-permeable, metabolically stable, and enables efficient cytosolic and nuclear delivery of diverse peptides and proteins in vitro and in vivo via recombinant fusion, serving as a general platform for intracellular protein delivery.

In this presentation, we will discuss strategies to enhance oral peptide bioavailability. This includes understanding the impact of peptide properties on oral absorption in the presence of permeation enhancers, as well as the effect of delivery site. Combining peptide engineering for oral delivery and formulation optimization for site-specific delivery can improve oral bioavailability. Additionally, we will present the controlled gastric delivery of a GIP/GLP-1 peptide in monkeys using mucoadhesive SNAC tablets.

Widespread use of peptide drugs like Ozempic raises concerns about the immunogenicity risks posed by generic versions. This presentation introduces orthogonal immunogenicity risk assessment methods for generic peptide drug impurities under the FDA’s Abbreviated New Drug Application (ANDA) pathway, focusing on two case studies: salmon calcitonin and teriparatide, to illustrate that understanding the inherent immunogenicity of the active pharmaceutical ingredient (API) is critical to estimating the potential immunogenicity of impurities.

Our work focuses on biointelligent biomaterial platforms that overcome the intrinsic barriers limiting peptide therapeutics.I will discuss how enzyme-responsive nanoparticles and hydrogels sense and respond to diseased microenvironments—stabilizing fragile peptides, navigating mucus and epithelial barriers, and localizing therapy with precision. These adaptive systems enable sustained delivery in the lung, mucosa, and osteoarthritic joints, opening new possibilities for clinically transformative peptide medicines.

MA-[D-Leu-4]-OB3 is a synthetic peptide leptin mimetic encompassing the functional epitope of the leptin molecule and engineered for optimal pharmacokinetics, efficacy, and oral or nasal administration. In mouse models of obesity, diabetes, and cognitive impairment, MA-[D-Leu-4]-OB3 has been shown to be safe and to have therapeutic and prophylactic efficacy. MA-[D-Leu-4]-OB3 reduces body weight gain, enhances insulin sensitivity, normalizes blood glucose, reverses diabetic dyslipidemia, promotes bone turnover, and enhances memory/cognition. Its ability to cross the blood-brain barrier, inhibit neuroinflammation and neurodegeneration, prevent/reduce beta-amyloid build-up, and improve cognitive function promises significant therapeutic benefit for an aging world population.