12.2 Synthetic biology approaches in drug discovery
3 min read•july 25, 2024
Synthetic biology is revolutionizing drug discovery by creating innovative tools and approaches. From for target validation to for high-throughput screening, it's transforming every step of the process.
These advancements are leading to more efficient drug development and novel therapeutic modalities. , , and are just a few examples of how synthetic biology is reshaping the future of medicine.
Drug Discovery Pipeline and Synthetic Biology Applications
Steps of drug discovery pipeline
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- Target identification and validation
- Synthetic biology creates disease models by engineering cells to mimic pathological conditions
- Engineered cell lines validate targets through controlled gene expression and pathway modifications
- Lead compound discovery
- Synthetic biology-based screening platforms utilize (yeast, bacteria) to produce and test compounds
- Biosensors enable high-throughput screening by detecting molecular interactions or cellular responses (fluorescence, )
- Lead optimization
- Metabolic engineering modifies compound structures through enzyme pathway alterations
- Directed evolution of enzymes improves catalytic efficiency and substrate specificity
- Preclinical studies
- Engineered animal models () more accurately represent human diseases
- In vitro mimic tissue-specific environments for drug testing
- Clinical trials
- Cell-based therapies use engineered cells (CAR-T cells) to target specific diseases
- Engineered probiotics serve as drug delivery vehicles, producing therapeutics in situ
- Manufacturing
- Biosynthesis of complex molecules uses engineered microorganisms to produce pharmaceuticals (artemisinin, insulin)
- allow rapid production of proteins without live cells
Synthetic biology in drug screening
- Engineered cellular reporters
- Fluorescent protein-based readouts quantify gene expression or protein interactions (GFP, RFP)
- Bioluminescent systems provide sensitive detection of cellular events (luciferase)
- Synthetic genetic circuits
- Logic gates enable multi-parameter screening by integrating multiple inputs
- Amplification cascades improve sensitivity through signal multiplication
- Microfluidic devices
- Droplet-based screening isolates single cells or compounds for high-throughput analysis
- Organ-on-a-chip platforms recreate tissue microenvironments for more physiologically relevant screening
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- track compounds in large-scale screens
- In vitro selection systems rapidly identify active compounds from vast libraries
- -based screening platforms
- systematically assess gene function in drug response
- modulate gene expression to identify drug targets or resistance mechanisms
Biosensors for drug optimization
- Principles of biosensor design
- Ligand-binding domains recognize specific molecules or interactions
- Signal transduction mechanisms convert molecular recognition into detectable outputs
- Types of biosensors
- detect small molecules and modulate gene expression
- monitor receptor activation and downstream signaling
- respond to metabolites by altering RNA structure and gene expression
- Applications in drug screening
- Target engagement assays directly measure drug-target interactions
- Functional readouts assess downstream effects of drug treatment
- Biosensor optimization strategies
- Protein engineering improves sensitivity through rational design or directed evolution
- Directed evolution enhances specificity by selecting for desired ligand interactions
- Integration with screening technologies
- Flow cytometry-based sorting enables rapid screening of large cell populations
- Microplate reader compatibility allows high-throughput quantitative measurements
Novel drug modalities from synthetic biology
- Engineered probiotics
- In situ drug production within the gut microbiome (insulin, antimicrobial peptides)
- Targeted delivery to specific gut regions or conditions
- CAR-T cell therapy
- Synthetic receptors improve targeting specificity and reduce off-target effects
- Inducible systems allow controlled activation of therapeutic cells
- Stem cell-based therapies
- Engineered differentiation pathways direct stem cells to desired cell types
- Synthetic niche environments support stem cell maintenance and differentiation
- Gene therapy vectors
- Engineered viral capsids enhance tissue tropism and reduce immunogenicity
- Non-viral delivery systems (lipid nanoparticles, DNA origami) improve safety and targeting
- Living therapeutics
- Bacteria serve as tumor-targeting agents, delivering drugs or stimulating immune responses
- Engineered phages combat antibiotic-resistant infections with high specificity
- Synthetic organs and tissues
- 3D-printed scaffolds with engineered cells recreate complex tissue structures
- Organoids enable personalized medicine through patient-specific drug screening
Key Terms to Review (32)
Activation/repression screens: Activation/repression screens are experimental techniques used to identify and analyze genetic elements that can enhance or inhibit gene expression. These screens help in uncovering regulatory mechanisms and pathways that could be harnessed for drug discovery, allowing researchers to determine how different factors can affect the production of therapeutic compounds.
Artificial insulin: Artificial insulin is a synthetic version of the hormone insulin, which regulates blood glucose levels in the body. This man-made hormone is crucial for individuals with diabetes, particularly Type 1 diabetes, who cannot produce sufficient insulin naturally. Advances in synthetic biology have allowed for the production of artificial insulin through recombinant DNA technology, making it possible to create large quantities that meet medical needs.
Bioluminescence: Bioluminescence is the natural phenomenon where living organisms produce and emit light, often through biochemical reactions involving luciferin and luciferase. This unique trait is commonly found in various marine species, certain fungi, and some terrestrial insects. Bioluminescence serves various ecological purposes such as attracting mates, deterring predators, and luring prey, making it a fascinating subject in fields like biosensor design and drug discovery.
Biosensors: Biosensors are analytical devices that convert a biological response into an electrical signal, allowing for the detection of specific substances or changes in biological conditions. They play a crucial role in various fields by providing real-time monitoring and analysis of metabolic processes, which can significantly enhance applications in metabolic engineering and synthetic biology.
CAR-T cells: CAR-T cells, or Chimeric Antigen Receptor T cells, are genetically modified T cells that express a receptor specifically designed to recognize and bind to a particular antigen on cancer cells. This innovative approach enhances the body's immune response against tumors, making CAR-T cell therapy a powerful tool in the treatment of certain types of cancer, particularly hematological malignancies. By engineering T cells to target cancer more effectively, this strategy showcases the intersection of synthetic biology and immunotherapy in drug discovery.
Cell-free protein synthesis systems: Cell-free protein synthesis systems are laboratory-based technologies that enable the production of proteins without the use of living cells. These systems use extracts derived from cells, such as ribosomes, enzymes, and other cellular machinery, to facilitate the transcription and translation processes necessary for protein synthesis. They offer advantages such as rapid production, flexibility in experimental design, and the ability to incorporate non-standard amino acids or modifications that may not occur in living organisms.
CRISPR: CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, is a revolutionary gene-editing technology derived from a natural defense mechanism found in bacteria. It allows scientists to make precise alterations to DNA sequences within organisms, which has opened up new avenues in research and therapy, particularly in genetic modification and synthetic biology applications. Its ability to target specific genes makes it an essential tool for advancing drug discovery and developing novel treatments.
Dna-encoded libraries: DNA-encoded libraries are collections of diverse DNA sequences that are linked to specific compounds, allowing for the screening of large chemical libraries in a highly efficient manner. These libraries enable researchers to rapidly identify and optimize potential drug candidates by connecting genetic information with chemical properties, streamlining the drug discovery process.
Engineered cell lines: Engineered cell lines are cells that have been genetically modified to express specific genes or proteins, enabling researchers to study biological processes or produce desired substances. These modifications can include the insertion, deletion, or alteration of genes, allowing for enhanced functionality or expression of therapeutic proteins. Engineered cell lines play a critical role in various applications, particularly in drug discovery and development, as they provide a controlled environment to test compounds and understand cellular responses.
Engineered microorganisms: Engineered microorganisms are microorganisms that have been genetically modified to perform specific functions, often utilizing synthetic biology techniques. These modifications can enhance their capabilities for tasks such as bioremediation, biofuel production, or drug synthesis, aligning with sustainability goals and innovative solutions in various fields, including healthcare and environmental management.
Engineered probiotics: Engineered probiotics are beneficial microorganisms that have been genetically modified to enhance their functionality, survival, or therapeutic properties. By altering their genetic makeup, these probiotics can be tailored to perform specific tasks, such as producing bioactive compounds or delivering drugs directly to targeted sites in the human body. This innovative approach not only improves the efficacy of probiotics but also allows for their use in advanced applications like drug discovery and disease prevention.
Fluorescent proteins: Fluorescent proteins are proteins that emit light when exposed to specific wavelengths of light, commonly used as markers in biological research. They allow scientists to visualize and track biological processes in real-time by tagging cells, proteins, or other molecules of interest. Their unique fluorescence properties make them invaluable tools in synthetic biology approaches, particularly in drug discovery.
Flux Balance Analysis: Flux Balance Analysis (FBA) is a mathematical approach used in systems biology and metabolic engineering to analyze the flow of metabolites through a metabolic network, allowing researchers to predict the output of cellular processes under defined conditions. It connects with various aspects of metabolic engineering by helping in optimizing the pathways for desired product formation, balancing fluxes through different metabolic routes, and improving the understanding of cellular behavior in response to genetic modifications.
Gene synthesis: Gene synthesis is the artificial creation of DNA sequences that can encode specific genes, using chemical processes to assemble nucleotides in a desired order. This technique allows scientists to design and produce custom genes tailored for various applications, such as creating new biological pathways or producing proteins with specific functions. Gene synthesis plays a critical role in the development of novel therapeutics and materials by enabling precise modifications at the genetic level.
Genome-wide knockout libraries: Genome-wide knockout libraries are collections of organisms, typically yeast, bacteria, or mammalian cells, that have been genetically modified to inactivate each gene in the organism's genome. This approach allows researchers to systematically study the effects of gene loss on various biological processes, particularly useful in drug discovery where understanding gene function can lead to identifying new therapeutic targets.
GMP Standards: GMP standards, or Good Manufacturing Practices, are a set of guidelines that ensure products are consistently produced and controlled according to quality standards. These practices are essential in the pharmaceutical and biotechnology industries, particularly in drug discovery, as they ensure the safety, quality, and efficacy of products intended for human use.
Gpcr-based biosensors: gpcr-based biosensors are innovative tools that utilize G protein-coupled receptors (GPCRs) to detect and quantify various biological signals, often in real-time. These biosensors leverage the natural signaling pathways of GPCRs to sense ligands, allowing for high specificity and sensitivity in drug discovery and therapeutic monitoring, making them essential in understanding cellular responses to potential pharmaceutical compounds.
Ligand-receptor binding: Ligand-receptor binding is the specific interaction between a ligand, which can be a molecule like a hormone or drug, and its corresponding receptor, typically a protein on the surface of a cell. This binding initiates a cellular response, triggering various signaling pathways that lead to changes in cell behavior or function. Understanding this process is crucial for developing targeted therapies in synthetic biology approaches, particularly in drug discovery, as it allows for the design of compounds that can effectively modulate biological activity.
Living therapeutics: Living therapeutics refer to engineered living systems, often using microorganisms, that are designed to deliver therapeutic effects in patients. These systems utilize principles from synthetic biology to create biological agents that can sense and respond to specific conditions within the body, aiming for personalized treatment strategies and improved health outcomes.
Metabolic Flux Analysis: Metabolic flux analysis (MFA) is a quantitative method used to analyze the flow of metabolites through metabolic networks, allowing researchers to understand the dynamics of metabolic pathways in cells. It integrates experimental measurements of metabolite concentrations and fluxes to provide insights into cellular metabolism, which is crucial for optimizing metabolic pathways, enhancing bioproduction, and engineering organisms for specific purposes.
Monoclonal antibodies: Monoclonal antibodies are laboratory-produced molecules engineered to serve as substitute antibodies that can enhance or mimic the immune system's attack on pathogens. They are identical immunoglobulins derived from a single clone of B cells, targeting specific antigens. Their precision in targeting makes them vital in drug discovery, particularly in developing therapies for diseases such as cancer and autoimmune disorders.
Organ-on-a-chip systems: Organ-on-a-chip systems are miniaturized devices that simulate the functions of human organs using living cells, allowing researchers to study biological processes in a controlled environment. These systems integrate microengineering, cell biology, and materials science to create a platform for testing drug responses and disease mechanisms, ultimately enhancing the drug discovery process.
Pathway Engineering: Pathway engineering is the systematic design, construction, and optimization of metabolic pathways to enhance the production of desired compounds in microorganisms or plants. This approach enables scientists to manipulate biological systems at a molecular level, integrating various biological components such as genes, enzymes, and regulatory elements to create efficient and productive pathways. The goal is often to improve the yield or efficiency of specific biochemical processes, making it an essential tool in both metabolic engineering and synthetic biology applications.
Pharmaceutical biotechnology: Pharmaceutical biotechnology refers to the use of biological systems, organisms, or derivatives to develop drugs and therapies that can treat diseases. This field combines principles from biology, chemistry, and engineering to create innovative solutions for drug discovery, development, and production, often leveraging genetic engineering and synthetic biology techniques to enhance efficacy and safety.
Protein-protein interactions: Protein-protein interactions refer to the specific ways in which two or more proteins bind and communicate with each other to perform biological functions. These interactions are crucial for various cellular processes, including signal transduction, enzyme activity regulation, and the formation of protein complexes. Understanding these interactions is essential for manipulating biological pathways in synthetic biology and drug discovery.
Riboswitches: Riboswitches are regulatory segments of RNA that can bind small molecules, resulting in changes in gene expression. They are part of a sophisticated system that allows cells to sense and respond to changes in their environment by modulating the transcription or translation of specific genes. This mechanism is important in synthetic biology as it can be harnessed for various applications, including the design of genetic switches and drug discovery.
Strain optimization: Strain optimization is the process of enhancing microbial strains or cell lines to improve their performance in producing desired compounds, such as pharmaceuticals or biofuels. This involves genetic modifications, metabolic pathway adjustments, and environmental condition changes to maximize yield and efficiency, ultimately leading to more effective drug discovery and development.
Synthetic circuits: Synthetic circuits are engineered networks of genetic components designed to perform specific functions in a biological system, similar to electronic circuits. These circuits allow for precise control over cellular behavior by integrating various regulatory elements, such as promoters, repressors, and other functional components. They are crucial in optimizing metabolic pathways, producing proteins, and discovering new drugs through innovative biological strategies.
Synthetic DNA barcodes: Synthetic DNA barcodes are short, unique sequences of nucleotides that are artificially designed and synthesized to label and identify specific biological entities. These barcodes provide a means of tracking genetic material, enabling researchers to monitor and analyze various biological processes, particularly in drug discovery efforts where identifying specific compounds and their interactions is crucial.
Systems Biology: Systems biology is an interdisciplinary field that focuses on understanding complex biological systems through the integration of various biological data and modeling techniques. It emphasizes the interactions between different components of biological systems, including genes, proteins, and metabolic pathways, to gain insights into their collective behavior and functionality. This holistic approach connects with diverse areas like synthetic biology, where it can enhance the design and engineering of biological circuits and optimize metabolic processes for applications in drug discovery and biosensing.
Transcription factor-based biosensors: Transcription factor-based biosensors are engineered systems that utilize transcription factors to detect specific biological molecules, triggering a measurable response, typically in the form of a reporter gene activation. These biosensors play a crucial role in synthetic biology, particularly in drug discovery, as they allow for the precise monitoring of cellular responses to various compounds. By coupling the detection of small molecules with transcriptional responses, these biosensors provide valuable insights into metabolic pathways and cellular functions.
Transgenic mice: Transgenic mice are genetically modified mice that contain a foreign gene, or transgene, which is incorporated into their genome. These mice serve as valuable models in research, especially for studying gene function, disease mechanisms, and testing new drugs in a controlled environment.