Oral & Macrocyclic Peptides: Discovery to Development – Part 1

Macrocyclic peptides are promising scaffolds for inhibiting protein-protein interactions. Here, we report a methodology for creating a cell-permeable and orally bioavailable peptide drug by identifying important factors for better drug-likeness and developing library technologies affording highly N-alkylated cyclic peptides. Several examples, including the latest findings, will be featured in this presentation.

Cyclins A/B orchestrate key activities throughout the cell cycle. Many substrates and regulators are recruited to the hydrophobic patch on Cyclins A/B through the interaction of their RxL-motif. This session will describe the development of macrocyclic peptide cyclin A/B RxL inhibitors which demonstrate tumor regression in CDX models of small-cell lung cancer via oral dosing. We are currently evaluating Cyclin A/B inhibition in a Phase 1 clinical trial (NCT06577987).

Orally bioavailable cyclic peptides represent a promising class of therapeutic agents, offering significant potential to address unmet medical needs across various disease areas. This presentation highlights the discovery and preclinical development of novel orally active cyclic peptide inhibitors targeting PCSK9 for the treatment of hypercholesterolemia. We will present and discuss preclinical data on SG6001, a preclinical compound identified by Sungening, demonstrating its promise as an effective oral PCSK9 inhibitor.

Interest in the discovery of peptide drugs is enjoying a resurgence, driven by the GLP-1 agonist class of anti-obesity medicines. Despite the demonstrated benefits of peptide therapeutics, developing oral drugs in this class has proved challenging, due to the difficulty of designing peptides that can cross the gut membrane. This talk will highlight work done at Unnatural Products aimed at developing generalizable approaches for oral delivery of peptide drugs.

Chromosomal instability (CIN) drives tumor progression and therapy resistance. KIF18A, a kinesin motor protein, maintains spindle integrity during mitosis, and its inhibition selectively kills CIN-high tumor cells while sparing normal cells. Using cryo-EM–guided design, we developed potent, selective macrocyclic KIF18A inhibitors with strong ATPase inhibition, anti-proliferative activity in CIN-high ovarian cancer cells, favorable ADMET and oral bioavailability, and significant in vivo efficacy, supporting their advancement as selective anti-CIN therapeutics.

Peptide hormones offer a versatile platform for engineering next-generation therapeutics. We present a rational design strategy that integrates structural insight, receptor pharmacology, and iterative optimization to tune potency, selectivity, and stability. By systematically combining modular sequence elements, we generate multifunctional peptide constructs that engage complementary pathways, highlighting general principles for translating natural signaling scaffolds into clinically promising metabolic drug leads.

D-peptides exhibit superior stability and reduced immunogenicity compared to L-peptides, yet their discovery has been constrained by traditional screening approaches. We present a computational framework for de novo design of D-peptides that accurately targets epitopes without requiring synthesis of D-enantiomeric proteins. This strategy enables efficient development of stable, nonimmunogenic peptide therapeutics, offering broad applicability and the potential to accelerate drug discovery across diverse biological targets.

Macrocyclic peptides are a compelling modality for disrupting protein-protein interactions. Beyond thioether formation and CuAAC, novel biocompatible cyclization methods are being developed to broaden the synthetic toolbox for macrocycle construction in both singleton and library formats. This presentation highlights our efforts to initiate new ring-closing chemistry and its integration into macrocyclic DNA-encoded library (DEL) platform for hit discovery.

Pure-DEL technologies features the solid phase-based synthesis of ultra-large libraries of highly-pure and chemically diverse DNA-encoded small macrocyclic peptides with drug-like properties. Pure-DELs can be screened at once in affinity-based selections and I will present the results of Pure-DEL selections for a variety of "undruggable" targets.

DNA encoded cyclic peptide library(DECPL) is a powerful platform for the cyclic peptide binder identification and optimization for biological interesting therapeutic targets with the advantage for the inclusion of thousands of unnatural amino acids and diverse cyclization methods for the library construction. The integration between mRNA Display and DNA Encoded Libraries could effectively accelerate the cyclic peptide drug development by speeding up the hit (generated by the mRNA display) to lead optimization. This talk will discuss the research progress on the technology development for the cyclic peptides optimization by joined efforts between mRNA Display and DECPL.

An oral therapy to treat the inflammatory components of CVD would have significant benefit by meeting unmet need for these patients.  mRNA-Display was leveraged to generate a macrocyclic peptide inhibitor of IL-1b as a starting point for molecular optimization.  High resolution crystal structures of these peptides bound to IL-1b provided inspiration for designs leading to enhanced potency.  Further optimization by improving solubility, proteolytic stability, and pharmacokinetics were driven by leveraging informatics and predicted properties to arrive at suitable candidates for large animal oral PK studies and in vivo PK/PD experiments.

Recombinant expression can efficiently and sustainably produce high-volume active pharmaceutical ingredients. However, this approach can also pose challenges to peptide drug design if a range of extensive post-recombinant chemistry is required to preserve drug-like properties.  Here, we present innovations in peptide chemistry to convert recombinantly expressed peptides into biologically active C-terminal a-amides, as well as key medicinal chemistry efforts, in the discovery of an oral, unimolecular GLP-1 and amylin agonist.

• Peptide synthesis and modification 
• Cardiometabolic disease
• Permeation enhancer-based oral delivery