Cyclic peptides are exciting new lead molecules for therapeutics. Graspetides are a class of RiPPs—ribosomally synthesized natural products—that harbor macrocyclic structures. I will describe our work on graspetide discovery, focusing on the biosynthesis of the graspetide fuscimiditide. Then, I will discuss how the key enzyme in fuscimiditide biosynthesis can be repurposed to cyclize short peptides with an arbitrary sequence, allowing for the construction of cyclic peptide libraries.

Cyclic peptides from soil-dwelling bacteria are a bountiful source of bioactive molecules, and the biosynthetic enzymes that produce them perform unique chemistries. Unfortunately, many biosynthetic gene clusters (BGCs) are cryptic. Herein, we are using bioinformatics predictions followed by direct chemical synthesis to access natural product-inspired cyclic peptides from cryptic BGCs followed by exploration of their bioactivities. Additionally, we have discovered biosynthetic enzymes capable of catalyzing cyclization of strained cyclic peptides.

Therapeutic peptides offer distinct advantages over small molecules but face delivery challenges. This presentation explores recent advances in peptide drug conjugates (PDCs) as targeting ligands and carriers for cytotoxics, radionuclides, and oligonucleotides. It also highlights long-acting injectable systems like nanofibrils and emerging oral delivery strategies using lipid-based formulations and permeation enhancers. By integrating molecular design with cutting-edge drug delivery technologies, we can overcome limitations in stability, bioavailability, and patient convenience—unlocking the full potential of peptide therapeutics.

Peptide design is used in combination with flash nanocomplexation (FNC) to produce uniform peptide-based particles of exceptional stability. FNC allows kinetic isolation of the mechanistic steps involved in particle formation facilitating the preparation of particles of discreet size in a highly reproducible, scalable, and continuous manner. We have prepared peptide-based miRNA particles for the treatment of mesothelioma and working towards pure peptidic particles for the delivery of therapeutic peptides.

I will discuss two synthetic —engineered— intrinsically disordered protein systems (SynIDPs) that we have developed that can be fused to peptide drugs at the gene level and enhance their in vivo delivery : 1) a SynIDP that undergoes thermally triggered liquid-liquid phase separation at body temperature upon subcutaneous injection and creates a depot that enables the sustained and tunable release of peptide drugs from a site; 2) a zwitterionic SynIDP that extends the plasma-half-life of peptide drugs fused to it.

Effective in vivo immune modulation requires coordinated antigenic and co-stimulatory signals to APCs. Yet current antigen-delivery approaches either fail to provide both signals or target only narrow sets of predefined antigens, allowing heterogeneous tumor subclones to escape and causing incomplete treatment or cancer relapses. We developed a carrier-free, self-assembling peptide–CDN nanoconjugate (PCN) that integrates immunogenic cell death (ICD) with cytosolic STING activation. Peptide library screening revealed that enriched hydrophobic and cationic residues promote self-assembly, cell penetration, and robust ICD via lysosomal and mitochondrial disruption, driving in situ antigen release. CDN conjugation further enables efficient cytosolic delivery and amplifies STING-dependent cytokine production and APC activation. PCN expands NK cells, tumor-specific CD8⁺ T cells, and memory T cells, producing complete tumor rejection in multiple models. This modular platform offers a generalizable strategy to co-deliver antigenic and co-stimulatory signals and overcome antigen heterogeneity.

Significant barriers face the development of therapeutics against key, complex intracellular proteins that drive cancer and neurodegenerative disease. These include barriers to administration including the blood brain barrier, tissue penetration barriers and of course the cellular membrane itself. However, most challenging remains the complex proteins and protein protein interactions themselves which remain elusive to small molecule and biological therapeutics. We present a new modality capable of overcoming each of these for selective and potent target engagement based on synthetic, precision polymer chemistry to design and develop proteomimetic therapeutics.

Self-assembly is a fundamental feature of intracellular processes, with proteins serving as primary building blocks. Inspired by protein assemblies regulated by enzymes, we developed enzyme-instructed self-assembly (EISA), which couples enzymatic reactions with self-assembly to convert small molecules into supramolecular nanostructures that modulate cell behavior. This talk will introduce the concept, simplicity, and uniqueness of EISA, focusing on its ability to generate intracellular peptide assemblies, including artificial filaments, within the cytosol. We will highlight examples of organelle-specific targeting (e.g., mitochondria, endoplasmic reticulum, Golgi apparatus, and nucleus) using enzymatically generated assemblies for therapeutic applications. Finally, we will discuss recent advances in leveraging EISA for transcytosis of peptide assemblies to control cell morphogenesis and spheroid formation. Together, these studies underscore the potential of EISA of intracellular peptide assemblies as versatile tools for manipulating cell behavior and advancing therapeutic strategies.

Bicycle molecules are bicyclic peptides formed by constraining short linear peptide sequences into a stabilized bi-cyclic structure using a central chemical scaffold. Bicycle molecules have a unique structure that can be engineered to deliver with high precision to their chosen targets, while their size and surface area means they can potentially engage targets that have historically been resistant to conventional modalities.

Nanobody and peptide conjugates are driving a new wave of precision therapeutics by combining highly selective binding with potent payload delivery.   Peptide conjugate therapies lead the way in the clinic with approved therapeutics and many in development, while there are significantly fewer nanobody conjugates that have only advanced to phase II.  I will review the competitive intelligence of this landscape with respect to radio-, oligo-, antibody-, and degrader drug conjugates.