Conjugates
Conjugates
Synthetic Conjugates
A peptide–drug conjugate (PDC) is a multifunctional molecule formed by linking a peptide to an active therapeutic agent (payload), resembling the structural concept of an antibody–drug conjugate (ADC). These conjugates are engineered to exploit the cell-penetrating and targeting properties of peptides, enabling efficient delivery of the payload directly into tumor cells. Upon internalization, the payload is released to exert its therapeutic effect precisely at the intended site. When properly designed, a PDC can achieve high efficacy and selectivity at very low doses. Sinopep specializes in producing all commonly used peptides involved in current PDC development, offering expertise in peptide synthesis, process optimization, and structural refinement. In addition, Sinopep provides advanced conjugation technologies, supporting the entire journey from early discovery to candidate development of peptide–drug conjugates.
Peptide-Oligonucleotide Conjugates
Synthetic oligonucleotides represent a promising class of therapeutics under development for a wide range of indications, including neurodegenerative diseases, ophthalmic disorders, cancer, respiratory conditions, and viral infections. Despite encouraging results, their broader clinical application is still limited by challenges such as poor cellular uptake and suboptimal pharmacokinetic properties, which can hinder both therapeutic efficacy and regulatory approval.
To address these limitations, chemical modifications of oligonucleotides—such as antisense oligonucleotides (ASOs), siRNA, CpG, miRNA, and aptamers—have become a focal point in drug development. Among these strategies, covalent conjugation with peptides has shown particular promise. Peptide-oligonucleotide conjugates (POCs) have demonstrated enhanced cellular uptake, including nuclear delivery, as well as improved tissue targeting and intracellular distribution.
In addition to POCs, advanced modalities such as peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) and peptide-drug conjugates (PDCs) are being actively explored to further expand the therapeutic potential of oligonucleotides and peptide-based delivery systems.
Conjugation Methods
Peptide–oligonucleotide conjugates (POCs) are assembled via diverse linkages—amide, disulfide, thioether, and triazole (Click Chemistry)—critical in POC therapeutic development. Peptides are most commonly linked at the 5′- or 3′-ends of oligonucleotides. For 5′-end conjugation, linker phosphoramidites are incorporated during standard solid-phase oligonucleotide synthesis. Various 5′/3′ modifiers, including thiols, alkynes, and amines, are available as derivatized phosphoramidites.
Conjugation Sites for POC Design
Multiple linkage positions—5′, 3′, and internal—enable flexible POC architectures, enhancing structural diversity during early-stage discovery.
3′-Amino Modifiers
Typically introduced as Fmoc-protected C7 CPGs, 3′-amino modifiers remain stable during synthesis but must be carefully deprotected to avoid side reactions. Alternatives like phthalimide-protected groups offer greater stability throughout oligo assembly.
Carboxy-Based Modifiers
Carboxy-linkers (e.g., NHS esters) at the 5′-end react with primary amines for amide bond formation. A hydrophobic C10 spacer minimizes steric hindrance during conjugation.
5′-Amino Modifiers
TFA- and MMT-protected 5′-amino phosphoramidites offer options for automated or manual synthesis. TFA forms are base-labile and suited for crude conjugation; MMT is preferred for purified fragments. Spacer lengths (C3, C6, C12) are commercially available.
Click Chemistry-Based Modifiers
CuAAC (Click Chemistry) forms triazoles via azide–alkyne cycloaddition under mild conditions. Alkyne groups are introduced at the 5′-end or internal bases using phosphoramidite modifiers. TIPS- or TMS-protected alkynes enable sequential click reactions post-purification. Copper-stabilizing ligands help prevent DNA damage.
Copper-Free Click Chemistry
To avoid copper-induced DNA damage, strain-promoted azide–alkyne cycloaddition (SPAAC) with cyclooctynes (e.g., DBCO) is used. 5′- or internal DBCO phosphoramidites are available for copper-free conjugation.
5′-Thiol Modifiers
Thiol-modified oligonucleotides offer reversible (disulfide) or stable (thioether) linkages. 5′-thiol modifiers include Trt-protected and disulfide-containing phosphoramidites, enabling purification via RP methods. Free thiols can be generated by reduction for peptide conjugation.
Disulfide and Thioether Linkages
Disulfide bonds form by reacting cysteine thiols with pyridyl disulfides. Thioethers are produced via Michael addition or substitution of haloacetamides, offering stable, non-reducible alternatives.
