Macrocyclic peptides are cyclized peptide structures (typically 5–15 amino acids) engineered to combine antibody-like target specificity with much better pharmacokinetics than linear peptides. The macrocyclization improves stability, membrane permeability, and oral bioavailability — opening targets that linear peptides and small molecules struggle to hit.
Key programs covered on this site include Circle Pharma's macrocyclic CID-078 (cyclin-targeting bicyclic peptide for RB1-deficient tumors), Bicycle Therapeutics' bicyclic platform, and academic structural biology papers on macrocyclic binding to KRAS, beta-catenin, and other intracellular protein–protein interaction targets.
The chemistry has been moving fast — peptide asparaginyl ligase (PAL) biocatalysis, AI-designed macrocycles, and biocatalytic cyclization platforms are reducing the cost and time per series. Stories here cover discovery papers, partnership deals, and clinical readouts. See #macrocyclic-peptides for the alternate tag.
A Nature Communications paper introduced a broad-spectrum macrocyclic peptide inhibitor designed for intranasal administration that protects against multiple SARS-CoV-2 Omicron variants in preclinical models. The work expands the macrocyclic peptide modality beyond oncology into respiratory antivirals, where peptide stability and tissue penetration challenges have historically limited clinical translation. Published as Nature Communications article s41467-026-68462-9.
A Nature Communications paper introduced CycloSEL (Cyclic Self-Encoded Libraries), an end-to-end workflow that screens synthetic macrocycle libraries enriched in drug-like 'beyond rule of five' features using affinity selections and tandem mass spectrometry — eliminating the genetic-barcode requirement of traditional macrocyclic peptide discovery. The team validated the approach against the oncology target carbonic anhydrase IX with a 16-million-member library, achieving robust enrichment and accurate identification of true binders. The platform shifts peptide drug discovery toward small molecule-like drug-likeness optimization from day one.
The AACR Annual Meeting 2026 concluded April 22 in San Diego after six days featuring unprecedented peptide-oncology visibility. Macrocyclic peptide drug conjugate (PDC) pipelines across Circle Pharma, Bicycle Therapeutics, Oncopeptides, and SignaBlok drew regulatory and venture attention; peptide-targeting radioligand data from Perspective Therapeutics, Bicycle, and AlphaGen signaled maturation of the peptide-radioconjugate subcategory. AACR Advances sessions throughout the meeting featured targeted protein degradation and novel tumor-selective modalities, with peptide-based approaches competing directly with antibody drug conjugates in Phase 1/2 readouts.
AlphaGen Therapeutics presented preclinical data at AACR 2026 (April 22) showing its novel macrocyclic peptide-based alpha-emitter radioligand [212Pb]Pb-AG1206 binds fibroblast activation protein with picomolar affinity, achieving rapid tumor accumulation, renal clearance, and a high tumor-to-kidney ratio. A sister candidate [212Pb]Pb-AG1002 targets SSTR2 as a non-agonist alpha therapy for neuroendocrine tumors.
Circle Pharma presents early clinical data for CID-078 in the AACR 2026 Clinical Trials Plenary (Sunday, April 19, 1:00-3:00 PT). CID-078 is a first-in-class orally bioavailable macrocyclic peptide cyclin A/B RxL inhibitor evaluated in a Phase 1 multicenter trial (NCT06577987) for advanced solid tumors with RB1 alterations. The plenary slot — a coveted showcase for private biotechs — tests whether macrocyclic peptides can establish themselves as a third modality alongside small molecules and biologics.
Circle Pharma presents "Orally Bioavailable Peptide Macrocycles Disrupting Intracellular Protein-Protein Interactions: Selective Inhibitors of the RxL-binding Site of Cyclin Family Proteins" at AACR's Chemistry to the Clinic Part 3 session on Saturday, April 18, 12:30-2:00 p.m. PST. The presentation covers CID-078, an orally bioavailable macrocycle with dual activity blocking cyclin A/B protein-protein interactions, selectively targeting tumor cells with RB1 alterations.
ApexOnco analysis frames AACR 2026 as a breakout moment for private peptide-based biotechs. Circle Pharma (macrocyclic peptides), Bicycle Therapeutics (bicyclic peptide drug conjugates), and SignaBlok (TREM-1 peptide) all landed prominent slots. Antibody-drug and peptide-drug conjugates remain the dominant theme, with conjugate-related abstracts outpacing any other modality in the clinical late-breaker sessions.
Circle Pharma secured a coveted oral plenary slot at AACR 2026 to present early Phase 1 clinical activity data for CID-078, a first-in-class orally bioavailable macrocyclic peptide cyclin A/B RxL inhibitor for patients with advanced solid tumors harboring RB1 alterations. The plenary (Sunday, April 19) validates macrocyclic peptides as viable oral oncology drugs — a major milestone for the modality.