Oligonucleotide Sequence Design & Discovery
The development of oligonucleotide therapeutics begins with the identification of suitable target sequences and the design of molecules with the desired biological activity, specificity, stability, and development potential. Protheragen provides integrated Sequence Design & Discovery services to support the early development of ASO, siRNA, PMO, and other oligonucleotide therapeutics. By combining target evaluation, sequence design, candidate screening, chemical modification strategies, and development-oriented optimization, Protheragen helps identify promising oligonucleotide candidates and establish a clear path toward downstream synthesis, CMC development, and manufacturing.
Overview of Oligonucleotide Sequence Design & Discovery
Sequence design is a critical step in oligonucleotide drug discovery because the biological activity of an oligonucleotide is closely associated with its sequence, target accessibility, molecular structure, and chemical characteristics. A rational design strategy can help identify sequences with appropriate target recognition while considering potential off-target effects, molecular stability, and downstream development requirements.
Candidate sequences can be evaluated based on target relevance, sequence specificity, predicted activity, chemical modification requirements, stability, and manufacturability. For therapeutic programs requiring targeted delivery, sequence design can also be integrated with conjugation strategies involving small molecules, peptides, antibodies, or other functional moieties. This integrated approach helps connect early candidate discovery with subsequent process development and manufacturing activities.
Fig.1 Mechanism of action of antisense oligonucleotides (ASOs). (Dhuri, K., et al., 2020)
Our Services
Protheragen provides integrated sequence design and discovery support tailored to the therapeutic mechanism, oligonucleotide modality, and development objectives of each program. From target and sequence evaluation to candidate screening, optimization, and development-oriented selection, our services help establish promising oligonucleotide candidates for subsequent CMC development and manufacturing.
Target and Sequence Evaluation
Protheragen evaluates target-related information and sequence characteristics to support the identification of suitable oligonucleotide candidates. Target accessibility, sequence specificity, biological mechanism, and potential unintended interactions can be considered during the early design stage.
Candidate Sequence Design
Candidate sequences are designed according to the intended therapeutic mechanism and oligonucleotide modality. Depending on the program, sequence design may support antisense-mediated gene regulation, RNA interference, or other sequence-dependent mechanisms.
Sequence Screening & Optimization
Multiple candidate sequences can be screened and compared to identify molecules with suitable activity and development characteristics. Selected candidates can undergo further optimization based on sequence performance, molecular properties, chemical modification, stability, and other development considerations.
Chemical Modification Strategy
Chemical modifications can be incorporated into sequence development strategies to improve properties such as nuclease resistance, molecular stability, pharmacological behavior, and overall development suitability. Modification selection is considered together with sequence characteristics and the intended mechanism of action.
Candidate Selection for Downstream Development
Candidate selection considers both biological performance and downstream development requirements. Protheragen can support the selection of candidates suitable for subsequent synthesis route development, CMC process development, analytical characterization, formulation development, and manufacturing.
Key Development Considerations
Sequence Specificity
Sequence specificity is fundamental to oligonucleotide therapeutics. Candidate sequences should provide appropriate target recognition while minimizing potential unintended interactions. Sequence evaluation and candidate comparison can therefore help establish a more suitable development profile.
Target Accessibility
The accessibility of the intended target can influence the effectiveness of sequence-dependent oligonucleotide mechanisms. Target characteristics and sequence context should be considered during candidate selection and optimization.
Chemical Modification
Chemical modifications can affect nuclease resistance, molecular stability, biological activity, pharmacokinetic properties, and other characteristics. Modification strategies should be evaluated together with sequence and therapeutic mechanism rather than treated as an independent design step.
Molecular Stability
Molecular stability can influence biological performance as well as downstream handling, purification, analytical characterization, formulation, and storage. Stability considerations are therefore incorporated into development-oriented candidate selection.
Off-Target Considerations
Potential unintended interactions are an important consideration during sequence selection. Candidate evaluation can incorporate sequence-specificity and off-target considerations to support the identification of candidates with appropriate development potential.
Manufacturability
Early consideration of synthesis, purification, analytical characterization, chemical modification, and scale-up requirements can help identify potential development risks before candidates enter CMC development.
Applications
Protheragen's Sequence Design & Discovery services can support the early development of:
- Antisense oligonucleotide (ASO) therapeutics
- Small interfering RNA (siRNA) therapeutics
- PMO therapeutics
- Chemically modified oligonucleotides
- Targeted oligonucleotide conjugates
- Oligonucleotide-small molecule conjugates
- Oligonucleotide-peptide conjugates
- Oligonucleotide-antibody conjugates
- Other emerging nucleic acid therapeutic modalities
Sequence Design & Discovery Workflow
The Sequence Design & Discovery workflow integrates target evaluation, sequence design, candidate screening, optimization, and development-oriented selection into a structured process. By considering biological activity, sequence specificity, chemical characteristics, and downstream development requirements at each stage, Protheragen supports the efficient progression of promising oligonucleotide candidates toward CMC development and manufacturing.
Applications of Oligonucleotide Discovery & Design
Our services can support the early development of:
- Antisense oligonucleotide (ASO) therapeutics
- Small interfering RNA (siRNA) therapeutics
- PMO therapeutics
- Chemically modified oligonucleotides
- Targeted oligonucleotide conjugates
- Oligonucleotide–small molecule conjugates
- Oligonucleotide–peptide conjugates
- Oligonucleotide–antibody conjugates
- Other emerging nucleic acid therapeutic modalities
Why Choose Protheragen
- Integrated Oligonucleotide Development
Protheragen connects sequence discovery and candidate design with subsequent conjugation, process development, analytical development, drug substance development, and manufacturing services.
- Development-Oriented Candidate Selection
Candidate evaluation considers not only biological objectives but also chemical characteristics, stability, synthesis requirements, analytical considerations, and downstream manufacturability.
- Support for Multiple Oligonucleotide Modalities
The service can support the development of ASOs, siRNAs, PMOs, chemically modified oligonucleotides, and targeted oligonucleotide conjugates.
- Conjugation Technology Integration
For programs requiring targeted delivery, sequence design can be coordinated with conjugation strategies involving small molecules, peptides, antibodies, and other functional components.
- CMC-Oriented Development Strategy
Early consideration of synthesis, purification, analytical characterization, stability, and scale-up requirements helps facilitate the transition from discovery candidates to CMC development.
- Seamless Transition to Manufacturing
Selected candidates can progress into Protheragen's downstream oligonucleotide CDMO workflow, including solid-phase synthesis route development, CMC process development, API development, analytical services, formulation, and manufacturing.
Protheragen provides integrated Sequence Design & Discovery services to support the identification and optimization of promising oligonucleotide therapeutic candidates. By considering target characteristics, sequence specificity, chemical modification, molecular stability, delivery requirements, and manufacturability, Protheragen helps clients establish development-ready candidates and transition efficiently from early discovery into CMC development and manufacturing. Contact us to discuss your oligonucleotide development program and identify an appropriate sequence discovery and development strategy.
Reference
- Moumné, L, et al. "Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development." J. Clin. Med., 2020; 9(6):2004.
