Custom Peptide-Oligonucleotide Conjugation Service
Introduction to Peptide-Oligonucleotide Conjugates (POCs)
A POC is a hybrid biomolecule that covalently links a peptide to a nucleic acid chain (an oligonucleotide). This innovative strategy merges the biological targeting capabilities of peptides with the genetic functionality of oligonucleotides, creating a powerful tool for advanced therapeutics and diagnostics. Peptides, as short chains of amino acids, can be designed to function as cell-penetrating modules or as high-affinity ligands for specific cell surface receptors. Oligonucleotides, such as DNA and RNA, can be engineered to modulate gene expression, correct genetic mutations, or silence disease-causing genes. By combining these two components, POCs overcome the primary challenge facing nucleic acid therapeutics: efficient and targeted delivery to the desired cells or tissues.
Fig.1 Challenges of systemic delivery of Oligonucleotide drugs.1
At Creative Biolabs, we specialize in the design and synthesis of diverse POC types tailored to your specific research goals:
Peptide-DNA Conjugates
These conjugates are engineered to deliver DNA payloads to specific cellular locations. They are instrumental in gene therapy applications, where the goal is to repair or replace faulty genes, and in developing advanced diagnostic probes that can detect specific genetic sequences within cells.
Peptide-RNA Conjugates
This class of POCs is central to gene silencing and regulation. By conjugating peptides to small interfering RNAs (siRNAs) or microRNAs (miRNAs), we enable targeted delivery to specific cell types, allowing for the potent and selective inhibition of disease-related gene expression.
Peptide-conjugated Phosphorodiamidate Morpholino Oligomers (PPMOs)
PPMOs combine a synthetic, uncharged nucleic acid analog (a PMO) with a cell-penetrating peptide (CPP). This design significantly enhances the cellular uptake of the PMO, making it a highly effective tool for antisense applications, such as correcting aberrant splicing in genetic disorders like Duchenne muscular dystrophy.
Advanced Conjugation Methods
The creation of a stable, functional, and pure POC requires mastery of complex bioconjugation chemistry. The selection of the appropriate linker and chemical reaction is critical to preserving the biological activity of both the peptide and the oligonucleotide. Our team possesses deep expertise in a comprehensive range of state-of-the-art conjugation techniques, allowing us to develop the optimal strategy for your project.
- Amide Coupling: This robust method forms a highly stable amide bond between an amino group on one molecule and a carboxylic acid on the other. It is a reliable and well-characterized technique for creating permanent linkages.
- Thiol-Maleimide Linkages: A cornerstone of "click chemistry," this reaction forms a stable thioether bond between a cysteine residue in a peptide and a maleimide-functionalized oligonucleotide. It is highly efficient and specific, proceeding rapidly in aqueous buffers.
- Cleavable Disulfide Bonds: For applications requiring the intracellular release of the oligonucleotide, we design POCs with disulfide linkers. These bonds are stable in the oxidative environment of the bloodstream but are readily cleaved within the reductive environment of the cell, liberating the therapeutic payload at its site of action.
- Azide-Alkyne Click Chemistry (CuAAC & SPAAC): Regarded as the gold standard for bioconjugation, copper-catalyzed (CuAAC) and strain-promoted (SPAAC) cycloadditions offer unparalleled specificity and efficiency. These reactions allow for the precise construction of complex POCs in high yields and purity, even with sensitive biomolecules.
Therapeutic and Diagnostic Applications
The ability to deliver oligonucleotide payloads to specific extra-hepatic tissues unlocks transformative potential across numerous fields of medicine. POCs are enabling researchers to pursue therapeutic strategies that were previously unattainable.
- Targeted Drug Delivery: This is the primary application of POCs. By using peptides that bind to receptors overexpressed in diseased tissues, we can concentrate therapeutic oligonucleotides precisely where they are needed, enhancing efficacy and minimizing systemic toxicity. Prominent examples include targeting the gastrin-releasing peptide receptor (GRPR) in prostate cancer, the HER2 receptor in breast cancer, and the glucagon-like peptide-1 receptor (GLP1R) on pancreatic β-cells for diabetes treatment.
- Gene Therapy and Repair: Peptide-DNA conjugates provide a promising vehicle for delivering gene-editing components or corrective gene sequences directly to the nucleus of target cells, offering potential cures for monogenic hereditary diseases.
- Gene Silencing: Peptide-siRNA conjugates are at the forefront of RNA interference (RNAi) therapeutics. This approach allows for the selective knockdown of proteins involved in cancer progression, inflammation, and viral infections.
- Advanced Diagnostics: POCs can be engineered as highly specific molecular probes. By conjugating a targeting peptide to a fluorescently labeled oligonucleotide, researchers can develop powerful imaging agents for detecting biomarkers or genetic mutations associated with early-stage disease.
Our Services
Creative Biolabs provides a comprehensive, end-to-end platform for the development and synthesis of custom POCs. We partner with our clients to translate innovative concepts into high-quality research tools and therapeutic candidates. Our services include:
Custom Peptide Design and Synthesis
We design and synthesize peptides with specific functionalities, including cell-penetrating sequences and high-affinity receptor ligands, incorporating modifications to enhance stability and performance.
Oligonucleotide Modification and Synthesis
We provide high-quality synthesis of DNA, RNA (siRNA, miRNA), and their analogs (e.g., PMOs), with a full range of chemical modifications to improve stability, reduce immunogenicity, and introduce reactive handles for conjugation.
Advanced Linker and Conjugation Strategy
Our experts will consult with you to select the optimal linker (cleavable or non-cleavable) and conjugation chemistry to ensure the final conjugate meets your project's specific stability, release, and activity requirements.
Purification and In-depth Characterization
We employ a suite of analytical techniques, including HPLC and mass spectrometry, to ensure the purification of your POC to the highest standard and to provide a comprehensive characterization and certificate of analysis.
Stability and Pharmacokinetic (PK/PD) Studies
To support the progression of your therapeutic candidate, we offer downstream services to assess the stability of your conjugate in biological matrices and to evaluate its pharmacokinetic and pharmacodynamic profile.
Our Advantages
Partnering with Creative Biolabs provides you with a distinct competitive edge in your research and development efforts. We are more than a service provider; we are your dedicated scientific collaborator.
Deep Technical Expertise: With over 20 years of experience in complex biomolecule synthesis, our scientific team possesses the deep knowledge required to overcome the most difficult challenges in POC design and production.
Collaborative Project Management: Each project is assigned a dedicated Ph.D.-level project manager who serves as your single point of contact, providing regular updates and expert consultation from initial design to final delivery.
End-to-End Platform: Our integrated facility houses all the necessary expertise and instrumentation under one roof. This eliminates the logistical complexities of working with multiple vendors and ensures a streamlined, efficient project timeline.
Commitment to Quality: Our operations are governed by a rigorous quality management system. We guarantee the purity, identity, and integrity of every conjugate we deliver, providing you with data you can trust.
Workflow
The therapeutic promise of oligonucleotides can only be realized through effective delivery. Peptide-oligonucleotide conjugates represent the key to unlocking that potential. At Creative Biolabs, we provide the specialized expertise and advanced technology to help you design and create the precise POCs needed to drive your research forward.
Ready to overcome your delivery challenges and accelerate your drug discovery program? Contact our specialists today for a confidential consultation and to receive a detailed project proposal.
Reference
- Anwar, Saeed et al. "Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies." Pharmaceutics vol. 15,4 1130. 3 Apr. 2023, doi:10.3390/pharmaceutics15041130. Under an open access license CC BY 4.0, without modification.