WDIC: Bio-orthogonal chemistry
Inside-molecule engineering
Okay, so that sounds scary, right? We’re here today for two reasons. First - it’s Monday, so I need to talk about something. But more importantly, I saw this extremely cool thing and have to tell you about it. It’s called bio-orthogonal chemistry (duh, it’s in the name), and three scientists secured a Nobel prize for that. Let’s dig into this and find out why:
What exactly are we talking about?
Bio-orthogonal chemistry is a field of chemical research that involves the development of new chemical reactions that are specific to biological molecules. These reactions allow for the study and manipulation of biological systems at the molecular level without affecting other cellular components. This approach has revolutionized biomedical research by enabling scientists to specifically target and study individual biomolecules within complex living systems.
What is the Noble Prize given for exactly?
Carolyn Bertozzi of Stanford University, Morten Meldal of the University of Copenhagen, and K. Barry Sharpless of Scripps Research won the Nobel Prize in chemistry on Wednesday for their development of click chemistry and bioorthogonal chemistry - methods that have been applied in drug development and studying disease. Click chemistry allows for molecules to be "clicked" together much more easily and precisely than traditional chemical reactions, with minimal chance for side reactions or unwanted products. This method has found use in drug development and delivery, DNA sequencing, functional materials, as well as studying biological processes - providing a better understanding of diseases and therapeutics to treat them.
Additionally, bioorthogonal chemistry developed by Bertozzi allows for tags to be attached to sugar molecules (glycans) on cells' surfaces without damage or interference from other biomolecules - Visualizing these glycans helps researchers understand how cells interact with each other and their environments.
What’s the history behind it?
The most common type of bio-orthogonal reaction is called click chemistry. Click reactions are extremely efficient and specific chemical reactions that can be used to attach small molecule probes or tags to proteins, DNA, and other biomolecules. The first click reaction was developed in 1996 by chemist K. Barry Sharpless, who demonstrated that the cycloaddition reaction between azides and alkynes could be used to covalently link small molecule probes to proteins (Sharpless, Kolb & Finn 1996). ‘
Since then, numerous other click reactions have been developed, each with its own unique features and benefits. For example, some click reactions can be performed in water, making them ideal for use in living cells. Other click reactions are “one-pot” reactions, meaning all of the reactants can be mixed together in a single vessel and allowed to react under conditions that are benign to cells (e.g., low temperature and oxygen levels).
Click chemistry has also been used to develop new methods for imaging living cells and tissues. For example, fluorescent tags can be attached to specific proteins using click chemistry, allowing those proteins to be visualized using fluorescence microscopy (FM). Similarly, magnetic resonance imaging (MRI) contrast agents can be covalently conjugated to biomolecules using click chemistry (Sarikaya et al., 2009).
In addition to its utility in biomedical research, bio-orthogonal chemistry is also being explored as a drug discovery and delivery tool. For instance, small molecule drugs can be “clicked” onto antibodies or other targeting moieties so that they are explicitly delivered to tumour cells (Cheng et al., 2010). This targeted delivery approach minimizes side effects by reducing the amount of drug that is exposed to healthy tissue.
Bio-orthogonal chemistry is an emerging field with great potential for impact in many areas of science and medicine. Its applications are limited only by the imagination of researchers who continue to find new ways to utilize this powerful tool.
What does the future hold for us?
Bio-orthogonal chemistry is a rapidly emerging field with great potential for broad impact in many areas, including drug development, diagnostics, and therapeutics. This new area of study takes advantage of the unique chemical properties of biological molecules to design novel compounds that can specifically target and modulate these molecules. The key to this approach is the use of small molecule probes that are "bio-orthogonal", meaning they can selectively interact with specific biological targets without disrupting other critical cellular processes.
One significant benefit of bio-orthogonal chemistry is its ability to enable precise targeting of drugs and other therapeutic agents to specific cells or tissues. For example, by attaching a bio-orthogonal moiety to a therapeutic compound, researchers can precisely deliver the compound to cancer cells while sparing healthy cells from its effects. This targeted approach has the potential to greatly improve the efficacy of drugs while reducing side effects. In addition, because bio-orthogonal probes can be designed to specifically bind to certain proteins or other biomolecules, they offer a powerful tool for studying the function of these molecules in health and disease.
Although still in its early stages, research on bioorthogonal chemistry is progressing quickly and has already yielded several promising results. In one recent study, researchers used a bio-orthogonal probe to successfully deliver an anti-cancer drug directly to tumour cells. In another study, scientists used a different type of bio-orthogonal probe to image receptors in the brain that are involved in Alzheimer's disease. These studies demonstrate the great potential of this approach for developing more effective treatments for cancer and other diseases.
Looking ahead, it is clear that bio-orthogonal chemistry holds tremendous promise for improving human health. As research in this area continues to advance, we can expect even more breakthroughs in developing targeted therapies for a wide range of conditions.
Where to expect the advancement from?
There are many different approaches that have been taken to develop bioorthogonal chemical probes. One common approach is to exploit the differences in chemical reactivity between native biological molecules and synthetic small molecules. For example, many biologically essential proteins contain disulfide bonds, which are relatively rare in small molecule compounds. This difference in reactivity can be exploited to develop probes that specifically target proteins containing disulfide bonds. Other examples include exploiting differences in nucleophilicity or electrophilicity or using unnatural amino acids as scaffolds for probe development.
In terms of specific researchers, there are many scientists working on developing bioorthogonal chemical probes. Some notable groups include those led by Drs. Dave Liu (Harvard University), Phil Baran (Scripps Research Institute), Matthew Bogyo (Stanford University), Jim Collins (Boston University), and Barry Sharpless (The Scripps Research Institute). These groups are just a few examples of the many active research groups in this field; new developments can be expected from all corners of the globe as this field continues to grow.
Thanks for reading! It was a complicated topic to unpack, and I’m happy that you went through that with me. As always, comment if you have something to add, or text me on Twitter if you have ideas for new posts at @Vaguelyprof.
Always yours,
Sean.