Cyclic peptides — including macrocyclic and bicyclic forms — are the structural class behind much of the modern undruggable-target peptide pipeline. Cyclization confers stability against proteases, improved membrane permeability, and stricter conformational lock that often translates to higher binding affinity.
Covered here: AACR 2026 readouts on cyclic peptides hitting intracellular targets, the University of Utah PapB radical-SAM thioether cyclization paper suggesting a route to GLP-1-like cyclic peptides without traditional medicinal chemistry, biocatalysis platforms based on peptide asparaginyl ligase (PAL), and the AI-design platforms generating cyclic candidates for KRAS and beta-catenin.
Stories here cover the chemistry, the discovery platforms, and the early-stage clinical work. See #macrocyclic-peptide and #bicyclic-peptide for narrower scopes.
20n Bio announced a $7.5 million Seed+ round May 20 led by a strategic industry investor with participation from a London-based life-sciences VC. Proceeds advance the company's high-throughput cyclic peptide platform — which screens libraries of up to 10 trillion sequences — and integrate AI into the discovery workflow. 20n is a Bayer Co.Lab resident and has a January 2026 long-term partnership with Yantai Lannacheng Biotechnology to develop next-generation radionuclide drug conjugates, leveraging Lannacheng's clinical translation and manufacturing for precision oncology programs.
TIDES USA 2026 opens in Boston May 11-14 with a featured presentation on Chugai's LUNA18 (paluratide), an N-alkyl-rich cyclic undecapeptide oral KRAS inhibitor. The corresponding paper in Organic Process Research & Development describes a convergent 24-step liquid-phase synthesis route delivering kilogram-scale GMP material at >98.5% purity and >30% overall yield. LUNA18 binds KRAS, NRAS, and HRAS mutants plus wildtype, inhibiting the inactive-state RAS-GEF protein-protein interaction; it achieves 21-47% oral bioavailability without special formulation. The molecule is in Phase 1 monotherapy and combination-with-cetuximab dose escalation. LUNA18's chemistry is a milestone for the oral-cyclic-peptide-against-intracellular-targets thesis that Bicycle Therapeutics, Circle Pharma, and Unnatural Products are advancing through different platform architectures.
Vertex Pharmaceuticals' Q1 business update confirmed continued enrollment and dosing in the multiple-ascending-dose portion of GALILEO, the global Phase 1/2 study of VX-670 in adults with myotonic dystrophy type 1, with results guided for H2 2026. VX-670 is an oligonucleotide linked to a cyclic peptide endosomal-escape vehicle from Entrada Therapeutics' EEV platform; the oligonucleotide engages CUG-repeat RNA to liberate bound MBNL1 splicing factor and correct the upstream missplicing that drives DM1 pathology. The trial is the first clinical readout for the Vertex–Entrada DM1 collaboration, originally signed February 2023 with $250M upfront. DM1 has no disease-modifying therapy.
A Nature Communications paper (2026) introduces CycloPepper, a machine-learning-guided platform for predicting cyclization outcomes and accelerating automated synthesis of therapeutic cyclic peptides. The model addresses one of the persistent bottlenecks in cyclic-peptide drug development: many promising linear sequences fail at the macrocyclization step or yield poorly under standard conditions, requiring expensive iterative chemistry. CycloPepper trains on a curated dataset of cyclization outcomes and integrates with automated synthesis platforms to enable closed-loop design-make-test cycles. The work joins CyclicMPNN (a fine-tuned ProteinMPNN derivative for cyclic peptide sequence design) and AfCycDesign as part of a fast-maturing computational stack for cyclic-peptide therapeutics.
A March 2026 bioRxiv preprint reports an AI-guided strategy for the discovery of cyclic peptide antagonists targeting the CD28 immune checkpoint, with the lead candidate CIP-3 binding the CD28 extracellular domain at nanomolar affinity and producing controllable modulation in cellular assays. CD28 is the principal T-cell co-stimulatory receptor and a high-value target for autoimmunity and transplantation, where current biologics (abatacept, belatacept) are large fusion proteins with associated dosing and immunogenicity tradeoffs. CIP-3's small cyclic-peptide format opens the prospect of subcutaneous dosing with a different PK profile. The work illustrates how AI-driven cyclic-peptide design is expanding beyond GLP-1 mimetics into immune-checkpoint pharmacology.
A May 2026 Drug Discovery World feature consolidates the case for cyclic peptides as a distinct therapeutic modality: larger and more selective than small molecules, more permeable and cheaper to manufacture than antibodies, and uniquely suited for protein-protein-interaction targets that have resisted traditional drug discovery. The piece traces the recent algorithmic stack — RFDiffusion adaptations for cyclic backbones, AfCycDesign, ProteinMPNN-derived sequence design — alongside the synthesis chemistry advances (one-pot ligations, photo-redox macrocyclizations) that turn computational hits into tractable scaffolds. Over 40 cyclic peptide drugs are now FDA-approved across endocrine, oncology, and antimicrobial uses, and 6+ peptide-drug conjugates sit in Phase 3, per the late-April PDC market analysis.
Lisata Therapeutics filed a May 3 SEC 8-K disclosing an Amendment and Waiver to the Merger Agreement with Kuva Labs Inc. The original definitive agreement (March 6, 2026) priced the all-cash tender at $5.00/share plus a $1.00 contingent value right per share — payable if a regulatory filing for certepetide is submitted or accepted in any jurisdiction within seven years. Closing is expected in Q2 2026. Certepetide is Lisata's cyclic peptide CendR-platform tumor-microenvironment modulator; the lead Phase 2 ASCEND trial in metastatic pancreatic ductal adenocarcinoma reported encouraging Cohort A data, and a Phase 1b/2a trial in locally advanced non-resectable PDAC is also active. Kuva is a cancer imaging company expanding into therapeutics through the deal.
Daiichi Sankyo's collaboration with Meddenovo's AI-powered Mexa technology — for de novo design of cyclic peptides — is among the highlighted partnerships at the Boston peptide summit. The deal positions Daiichi to leverage Meddenovo's machine-learning platform for peptide candidates beyond the company's traditional small-molecule oncology focus. Cyclic peptide AI design is one of the fastest-moving subcategories in peptide drug discovery, with Circle Pharma, Bicycle Therapeutics, and Unnatural Products all pursuing distinct platform architectures.
A Nature Communications paper published April 27 mined natural diversity in Viola plants to discover 29 new peptide asparaginyl ligases (PALs) — enzymes that catalyze cyclization of synthetic peptide chains. The work characterizes a pH-dependent cyclization mechanism and defines transferable expression-increasing principles, substantially expanding the enzymatic toolkit available for cyclic peptide drug development. The discovery is timely given the surge of macrocyclic peptide programs at Circle Pharma, Bicycle Therapeutics, and Unnatural Products.
A team at Kumamoto University led by Associate Professor Shingo Ito developed a cyclic peptide (D-DNP-V) that ferries insulin across the small intestine. Combined with zinc-stabilized insulin hexamers and given orally to diabetes models, the platform rapidly normalized blood sugar with once-daily dosing for three consecutive days. A click-chemistry-conjugated DNP-insulin molecule performed equivalently, substantially reducing the high doses that have historically plagued oral insulin.
The Drug Discovery Chemistry Oral & Macrocyclic Peptides Summit (April 14-15, San Diego) convenes as 66 cyclic peptide drugs have gained global approval and the field races to solve oral bioavailability. Key advances include Chugai's Luna18 achieving 21-47% oral bioavailability and Merck's macrocyclic PCSK9 inhibitor enlicitide delivering injectable-level results in pill form.
Kumamoto University's DNP cyclic peptide system achieved roughly one-third to nearly half the effectiveness of injected insulin in animal studies — a major advance for oral insulin delivery.
Kumamoto University researchers developed cyclic peptide D-DNP-V that escorts insulin through the gut, achieving one-third to nearly half the effectiveness of injected insulin in mice.
Kumamoto University researchers developed a cyclic peptide (DNP peptide) that enables oral insulin delivery through the intestinal wall — a dramatic improvement that could end the century-long dependence on injections.