Hey, my name is Angel and I would like to explain a bit about bio-conjugation in the space between organic synthesis and biochemistry
The world of biochemistry entails the understanding of biological processes at the cellular and molecular level, where a plethora of interactions between macro and small molecules take place. It is a complex system, where variables are hard to control and assess. This is in stark contrast to organic chemistry, the world of special glassware, where reactions usually happen in small molecules, one change at the time, and the variables are highly controlled. Yet, despite their differences, there is a symbiotic element between the two. The understanding of biochemistry and its convoluted processes open a window for the development of applications that can be achieved exploiting organic synthesis and organic chemistry. On the other hand, organic synthesis, in the pursue of these applications, is enriched and expanded, to accommodate the new challenges it has to accomplish.
An example of this symbiosis is the development of antibody conjugates. Antibodies are a special kind of protein, recognizable by their “Y” shape and its massive size (for molecular standards). They are a key part of the immune response, being able to tag specific targets such as virus, cancerous cells or microbes for either direct neutralization, or as a signal for other components of the immune system to destroy. The high selectivity of these macromolecules to specific targets is something that small molecules are not able to do. Researchers exploiting the tools availed by organic synthesis, developed a method to link small molecules of interest (a payload), to this “seeker” macromolecule, creating the conjugates.
This approach creates new kind of drugs that deliver payloads to specific targets, with less affect to healthy cells. Organic chemists has developed an array of protocols to attach payloads to antibodies; these payloads can vary widely, from toxic drugs, fluorophores (molecular lightbulbs), and radioactive ions to even other macromolecules (nucleic acids, lipids, peptides and other proteins). The wide number of options allows researcher to construct bio-molecular devices to monitor, diagnose and treat pathogens in highly selective ways.
Artificial and modified nucleic acids exemplify another instance of this organic synthesis-biochemistry dance, where development of small molecules analogues to natural nucleosides are synthesized as building blocks for these artificial nucleic acids. Short strands of artificial nucleic acids are constructed via solid phase synthesis using reaction cycles, alternating the different nucleobases to generate the specific sequence. Artificial nucleic acids analogues has several advantages over DNA and RNA. Firstly, they are not cleared nor degraded by the body as fast as normal DNA/RNA, also, depending on the case; they might hybridize with higher affinity to a complementary strand, when compared to their natural counterparts. These characteristics make artificial nucleic acids analogues, good candidates for potential therapeutic uses, such as antisense therapy.
Designing new molecules is like solving a puzzle. The researcher must find a way to synthesize a structure with the different functional groups, playing with the different commercial building blocks, and finding a proper order and protocols to assemble it. The last step is the most crucial, since many functional groups can be degraded by reaction conditions, and different functional groups can be incompatible with each other, leading to unstable molecules. A tool researchers use is Reaxys, the “google” of organic synthesis. It works as vast repository of synthetic protocols, and allow you to search by structure, structural changes, type of reactions, etc. The repository holds arguably millions of reactions and examples. It is a great tool to find reaction “recipes” and plan your synthetic routes.
The game then moves to the organic laboratory. Here you follow the reaction protocol, as a baker follows a recipe. It involves knowledge, experience and practice, but a good chemist can pull out a clean and nice molecule, playing with glassware, solvents and purification techniques.
Once the small molecules syntheses are completed, it is the turn of biochemistry, where Eppendorf tubes and pipettes are the tool of choice. Here aqueous solutions are mixed and the different component left to react, helped by some organic solvents as DMSO or DMF, then purified by specialized methods, such as gel electrophoresis or HPLC. This conjunction of scientific areas leads to the creation of biologic macromolecules that will be the drugs and biotech devices of the future.
If you found this small lecture interesting, you can go into the scientific rabbit-hole with some nice review papers:
- Agarwal, P.; Bertozzi, C. Site-Specific Antibody–Drug Conjugates: The Nexus of Bioorthogonal Chemistry, Protein Engineering, And Drug Development. Bioconjugate Chemistry 2015, 26 (2), 176-192. https://pubs.acs.org/doi/10.1021/bc5004982
- Dugal-Tessier, J.; Thirumalairajan, S.; Jain, N. Antibody-Oligonucleotide Conjugates: A Twist To Antibody-Drug Conjugates. Journal of Clinical Medicine 2021, 10 (4), 838. https://www.mdpi.com/2077-0383/10/4/838/htm
- Roberts, T.; Langer, R.; Wood, M. Advances In Oligonucleotide Drug Delivery. Nature Reviews Drug Discovery 2020, 19 (10), 673-694. https://www.nature.com/articles/s41573-020-0075-7