Custom terminus-to-side-chain cyclic peptide synthesis (N→SC and C→SC) with rational linkage placement and fit-for-purpose QC.
Bio‑Synthesis provides custom terminus‑to‑side‑chain cyclic peptide synthesis—including head‑to‑side‑chain (N→Side) and tail‑to‑side‑chain (C→Side) macrocycles—with linkage selection, clean cyclization, purification, and fit‑for‑purpose QC for discovery, receptor ligands, protease‑resistant scaffolds, and SAR studies.
A macrocycle formed by linking one peptide terminus (N or C) to a selected residue side chain (commonly Lys ε‑amine, Asp/Glu side‑chain carboxylate, or Cys‑derived linkage). This topology constrains conformation while optionally leaving the other terminus free or capped.
Common synonyms: terminus‑to‑side‑chain macrocycle, head‑to‑side‑chain cyclization, tail‑to‑side‑chain cyclization, lactam‑bridged cyclic peptide.
Choose the topology based on which terminus must remain available after cyclization. We recommend the most practical approach after reviewing your sequence and application.
Related services: Macrocyclic peptides • Stapled peptides • Difficult peptide synthesis • Click chemistry peptides
In N→Side (head-to-side-chain), the N-terminus is consumed and the C-terminus remains free/capped. In C→Side (tail-to-side-chain), the C-terminus is consumed and the N-terminus remains free/capped. Bridge chemistry and anchor selection (Lys/Asp/Glu/Cys) are chosen to preserve the pharmacophore and improve closure efficiency.
For sequences prone to intermolecular coupling during N→C cyclization, terminus‑to‑side‑chain designs can provide a cleaner route to single‑macrocycle products.
Concept schematic (not atom‑accurate). Linkage geometry and bridge placement are sequence‑dependent.
Some constructs combine terminus‑to‑side‑chain cyclization with a second constraint (e.g., additional side‑chain bridge, disulfide, staple, or handle‑based linkage) to further rigidify conformation or probe SAR. These architectures typically require careful orthogonal protecting‑group strategy and stepwise LC‑MS verification.
Robust amide bridges using Lys/Asp/Glu functional groups. A go-to choice when you need stability and tunable bridge placement.
Stable linkage when cysteine placement enables chemoselective coupling; often used when disulfides are unstable in your system.
Handle-based strategies when orthogonality matters; useful in multi-step conjugation workflows.
Single-view workflow summary. Topology selection (N→Side vs C→Side), cyclization strategy, LC-MS monitoring, and purification are tuned to minimize dimerization and deliver fit-for-purpose QC.
Terminus-to-side-chain cyclization is usually selected because you want a macrocycle while keeping either the N-terminus or C-terminus free (or capped in a defined way). Start with the terminus requirement, then confirm bridge chemistry and anchor placement.
When you need a free C-terminus (native C-end, charge tuning, receptor engagement motifs, or downstream conjugation).
When you need a free N-terminus (labels, click handles, affinity tags, or native N-terminal function).
If you need no free termini for maximal exopeptidase resistance, consider head-to-tail (N→C) cyclization.
Recommendations for N→SC vs C→SC and bridge chemistry based on motif, assay conditions, and conjugation needs.
Orthogonal protection to enable selective cyclization and suppress side reactions.
Cyclization conditions tuned to reduce oligomers; LC-MS checkpoints for conversion and identity.
Prep HPLC purification with salt exchange/lyophilization options.
Analytical HPLC + MS (or HRMS) + COA; additional characterization available.
Repeatable production and documentation continuity for ongoing programs.
Connect backbone modification with constrained scaffolds, labeling, and challenging sequences.
Specified mg quantity and target purity (commonly ≥95% when feasible).
Analytical HPLC chromatogram(s) plus MS confirmation; HRMS optional.
Certificate of Analysis documenting identity and purity.
Keep a terminus free for dyes, biotin, or click handles while adding macrocyclic constraint.
Topology control can improve binding reproducibility and stability in assay buffers.
Compare matched cyclic topologies to identify the stability/conformation combination that drives function.
We manage concentration and addition mode, control solubility/aggregation, use orthogonal protection, and monitor by LC-MS. Linkage placement and turn propensity are reviewed during design.
Typical deliverables include purified peptide, analytical HPLC chromatograms, MS (or HRMS) confirmation, and a COA; additional characterization is available based on application.
Common anchors include Lys (ε-amine), Asp/Glu (side-chain carboxylates), and Cys (thiol-based chemistries). The best choice depends on desired linkage stability, bridge length, and whether anchors overlap with functional residues.
Common approaches include lactam bridges (amide linkages using Lys/Asp/Glu), thioether linkages via cysteine chemistry, and other chemoselective strategies depending on functional group availability and protection strategy.
Analytical HPLC often shows new higher-retention peaks or broad shoulders, and MS reveals mass multiples consistent with dimer/oligomer series. Dilution, slow addition, solubility control, and linkage/topology changes are typical fixes.
Choose terminus-to-side-chain when you need a free terminus, want flexible linkage placement away from the pharmacophore, or want to reduce oligomerization risk compared with N-to-C closure for certain sequences.
State the required free terminus (N or C), whether it should be unmodified or capped (e.g., acetylated/amidated), and any intended labels/handles. We will recommend N→SC vs C→SC topology and a protection plan aligned to that requirement.
Tail-to-side-chain cyclization links the C-terminus to a side chain, which can preserve a functional N-terminus for labeling, conjugation, or activity requirements.
A head-to-side-chain cyclic peptide forms a covalent bond between the N-terminus and a selected residue side chain (commonly Lys, Asp/Glu, or Cys-derived linkages), creating a macrocycle while allowing the C-terminus to remain free or capped.
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Selected peer-reviewed references on cyclic peptides, terminus-to-side-chain cyclization, and macrocycle design principles relevant to stability, conformation, and SAR.
If you are interested in related architectures, see also Head-to-Tail Cyclic Peptides, Side-Chain Cyclic Peptides, Macrocyclic Peptides, and Difficult Peptide Synthesis
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