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Can drugs be made without cells? This technology is shattering the “impossibility” of peptide therapeutics.
Release date:
2026-05-21
In the biomedical field, peptides hold a critical position as therapeutics, playing key roles in disease-related metabolic reprogramming and immune regulation. Thanks to their excellent biocompatibility and high specificity, they have become a highly reliable choice for clinical treatments.
However, in the race to develop peptide drugs, researchers often encounter a stark gap between theoretical promise and practical reality. Candidate molecules such as antimicrobial peptides (AMPs) and ribosomally synthesized and post-translationally modified peptides (RiPPs) demonstrate exceptional pharmacological activity, yet their development process is notoriously grueling. Traditional cell-based expression systems act much like a closed "black box," severely limited by constraints like host cytotoxicity and poor membrane permeability.
Figure 1: Peptide-based drug discovery [1]
1. Addressing the Bottlenecks: Why Peptide R&D Needs a "Cell-Free" Approach
Cell-Free Protein Synthesis (CFPS) technology is rapidly emerging as a disruptive tool in the peptide research space, characterized by its openness, flexibility, and high efficiency. Choosing CFPS is no longer just chasing a trend—it is an essential solution to real-world bottlenecks.
- Bypassing Host Toxicity: Many peptides with potent antimicrobial or cytotoxic properties will directly "kill" the host when expressed in live cells, resulting in extremely low yields or complete expression failure. The CFPS system takes place entirely in vitro, completely circumventing this issue and ensuring that "toxicity" is no longer a barrier to expression [2].
- An Open Reaction Environment: Free from the constraints of a cell membrane, researchers can precisely control every component within the reaction system. Whether adjusting the redox potential to assist in disulfide bond formation or introducing non-canonical amino acids (ncAAs) to endow peptides with novel functions, CFPS offers unparalleled controllability [3].
- Rapid "DNA-to-Protein" Workflow: The lengthy cycles of traditional cloning, transformation, induction, and purification are drastically compressed. CFPS can typically synthesize active proteins directly from a DNA template within a few hours to a day, dramatically accelerating the "Design-Build-Test-Learn" (DBTL) R&D cycle [4].
2. Real-World Applications: CFPS Breakthroughs in the Peptide Landscape
Unlocking the Synthesis Codes of Complex Modified Peptides [5]
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural products known for their powerful biological activities, universally exhibiting potent antimicrobial, antiviral, and antitumor properties. However, traditional cellular expression of RiPPs struggles with poor compatibility between modifying enzymes and substrates, alongside uncontrollable synthesis and regulation.
Liu WQ et al. developed a unified biocatalytic system (UniBioCat) based on CFPS technology for the rapid biosynthesis and engineering of RiPPs. Compared to traditional cellular pathways, CFPS shortens the novel peptide discovery cycle from months down to mere days. Furthermore, it enables the direct expression of toxic peptides encoded in genomic dark matter, vastly expanding the screenable chemical space.
Figure 2: Biosynthesis of RiPPs using the UniBioCat platform
AI + CFPS: An Intelligent Closed Loop for Peptide Drug Discovery [6]
Bioactive peptides are crucial molecules in health and medicine, and deep learning brings tremendous potential to their discovery and design. However, validating these candidate molecules requires experimental methods capable of high throughput and low cost. Pandi et al. established a CFPS pipeline that enables the rapid, cost-effective production of AMPs directly from DNA templates. Their research demonstrated the potential of CFPS to achieve high-throughput production and testing of bioactive peptides within a 24-hour window.
If CFPS is the powerful executor, Artificial Intelligence (AI) is the master brain. The integration of the two is actively reshaping the paradigm of peptide drug discovery.
Figure 3: Workflow for de novo development of AMPs via deep learning and cell-free biosynthesis
Non-Canonical Amino Acids: Giving Peptides "Superpowers"
Driven by advances in modern chemistry and biology, non-canonical amino acids (ncAAs) have become powerful tools in the development of peptide drug candidates. While peptides composed of natural amino acids are viable drug candidates, most suffer from poor stability under biological conditions. Integrating ncAAs plays a vital role in modulating a peptide's stability, potency, permeability, oral bioavailability, and immunogenicity [7].
Traditional cell-based methods face significant roadblocks here, such as low insertion efficiency and a lack of stability. Some ncAAs simply cannot be utilized intracellularly, and host cell metabolism strictly limits experimental conditions. CFPS possesses a natural advantage in integrating ncAAs. Through orthogonal translation systems, researchers can precisely insert ncAAs equipped with specific functional groups (e.g., azide or alkyne groups) at targeted sites within the peptide [8].
Figure 4: The CFPS workflow
3. Conclusion and Future Outlook
CFPS has evolved far beyond a mere production tool; it is now a disruptive platform for the discovery, optimization, and manufacturing of peptide drugs. By cracking the cytotoxicity bottleneck with its open environment, achieving complex post-translational modifications through precise regulation, and syncing seamlessly with AI-driven design via its high-throughput capabilities, CFPS demonstrates irreplaceable advantages—especially for hard-to-express molecules like RiPPs, AMPs, and lasso peptides.
From the integrated synthesis of UniBioCat to the intelligent closed loop of AI-CFPS, the trajectory is clear. As cell-free systems undergo further optimization, microfluidic CFPS becomes widespread, and AI predictive accuracy improves, CFPS will be deeply integrated into the entire lifecycle of peptide drugs. This will drastically shorten R&D timelines, reduce costs, and increase success rates, providing us with more robust molecular weapons to conquer major diseases such as infections, pain, and cancer.
As a pioneering manufacturer and innovator in the field of Cell-Free Protein Synthesis (CFPS), PLD Technology is dedicated to providing cutting-edge solutions, high-throughput workstations, and core reagents for the global biopharma industry. We are actively expanding our global market presence and warmly welcome professional agents to partner with us. For technical inquiries, product portfolios, or to discuss distributorship opportunities, please reach out to us at bd@sz-pld.tech.
References
[1] Sharma, Komal et al. “Peptide-based drug discovery: Current status and recent advances.” Drug discovery today vol. 28,2 (2023): 103464. doi:10.1016/j.drudis.2022.103464.
[2] Chen JP, Gong JS, Su C, Li H, Xu ZH, Shi JS. Improving the soluble expression of difficult-to-express proteins in prokaryotic expression system via protein engineering and synthetic biology strategies. Metab Eng. 2023;78:99-114. doi:10.1016/j.ymben.2023.05.007.
[3] Martin, Rey W et al. “Cell-free protein synthesis from genomically recoded bacteria enables multisite incorporation of noncanonical amino acids.” Nature communications vol. 9,1 1203. 23 Mar. 2018, doi:10.1038/s41467-018-03469-5.
[4] Landwehr, Grant M et al. “Accelerated enzyme engineering by machine-learning guided cell-free expression.” Nature communications vol. 16,1 865. 20 Jan. 2025, doi:10.1038/s41467-024-55399-0.
[5] Liu WQ, Ji X, Ba F, et al. Cell-free biosynthesis and engineering of ribosomally synthesized lanthipeptides.Nat.Commun.2024;15(1):4336.Published 2024 May 21. doi:10.1038/s41467-024-48726-y.
[6] Pandi, Amir et al. “Cell-free biosynthesis combined with deep learning accelerates de novo-development of antimicrobial peptides.” Nature communications vol. 14,1 7197. 8 Nov. 2023, doi:10.1038/s41467-023-42434-9.
[7] Sharma KK, Sharma K, Rao K, et al. Unnatural Amino Acids: Strategies, Designs, and Applications in Medicinal Chemistry and Drug Discovery. J Med Chem. 2024;67(22):19932-19965. doi:10.1021/acs.jmedchem.4c00110.
[8] Martin, Rey W et al. “Cell-free protein synthesis from genomically recoded bacteria enables multisite incorporation of noncanonical amino acids.” Nature communications vol. 9,1 1203. 23 Mar. 2018, doi:10.1038/s41467-018-03469-5.
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