glycans
The Chemistry Clicked: Two NIH-Supported Researchers Win 2022 Nobel Prize in Chemistry
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Through the years, NIH has supported a total of 169 researchers who have received or shared 101 Nobel Prizes. That’s quite a testament to the world-leading science that NIH pursues and its continued impact on improving human health and well-being.
Those numbers include the news late last week that the 2022 Nobel Prize in Chemistry was shared by two long-time grantees for their work on a transformative scientific approach known as “click chemistry.” This form of chemistry has made it possible for researchers to snap together, like LEGO pieces, molecular building blocks to form hybrid biomolecules, often with easy-to-track imaging agents attached. Not only has click chemistry expanded our ability to explore the molecular underpinnings of a wide range of biological processes, but it has provided us with new tools for developing drugs, diagnostics, and a wide array of “smart” materials.
For K. Barry Sharpless, Scripps Research, La Jolla, CA, October 5, 2022 marked the second time that he’s received an early-morning congratulatory call from The Royal Swedish Academy of Sciences. The first such call came in 2001, when Sharpless got the news that he was a co-winner of the Nobel Prize in Chemistry for his discovery of asymmetric catalytic reactions.
This time around, Sharpless was recognized for his groundbreaking studies in the mid-1990s with click chemistry, a term that he coined himself. His initial work established click chemistry as a fast-and-reliable way to attach molecules of interest in the lab [1]. He and co-recipient Morten Meldal, University of Copenhagen, Denmark, who is not funded by NIH, then independently introduced a copper-catalyzed click that further refined the chemistry and helped popularize it across biology and the material sciences [2,3].
For Carolyn R. Bertozzi of Stanford University, Palo Alto, CA, it is her first Nobel. Bertozzi was recognized for expanding the use of click chemistry with so-called bioorthogonal chemistry, which is a copper-free version of the approach that can be used inside living cells without the risk of metal-associated toxicities [4,5].
Bertozzi’s work has been especially interesting to me because of her focus on glycans, which I’ve studied throughout my career. Glycans are the carbohydrate molecules that coat the surfaces of our cells and most secreted proteins. They are essential to life, and, in higher organisms, play fundamental roles in basic processes such as metabolism, immunity, and cellular communication.
Glycans also remain poorly understood, largely because, until recently, they have been so difficult for basic scientists to study with traditional techniques. That has changed with development of new tools to study glycans and the enzymes that assemble them. My long-time collaborator, Kelly Ten Hagen, a senior investigator at NIH’s National Institute of Dental and Craniofacial Research, and I collaborated with Carolyn on identifying small molecules that inhibit the enzyme responsible for the first step in mucin-type O-glycosylation [6]
In the early 2000s, Bertozzi and her team introduced bioorthogonal chemistry, which enabled researchers to label glycans and visualize them in a range of cells and living organisms. Her team’s pioneering approach quickly became an essential tool in basic science labs around the world that study glycans, leading to a number of stunning discoveries that would have otherwise been difficult or impossible.
For clinical researchers, click chemistry has emerged as a workhorse in drug discovery and the improved targeting of cancer chemotherapies and other small-molecule drugs. The approach also is being used to improve delivery of antibody-based therapies and to create new biomaterials. Meanwhile, in the material sciences, click chemistry has been used to solve a number of problems in working with polymers and to expand their industrial uses.
Click chemistry is an excellent example of how advances in basic science can build the foundation for a wide range of practical applications, including those aimed at improving human health. It also highlights the value of strong, sustained public funding for fundamental research, and NIH is proud to have supported Sharpless continuously since 1975 and Bertozzi since 1999. I send my sincere congratulations to both of these most-deserving scientists.
References:
[1] Click Chemistry: Diverse chemical function from a few good reactions. Kolb, HC, Finn, MG, Sharpless, KB. Angew. Chem. Int. Ed. 2001, 40 (11), 2004–2021
[2] A stepwise huisgen cycloaddition process: Copper(I)-catalyzed regioselective “Llgation” of azides and terminal alkynes. Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002, 41 (14), 2596–2599.
[3] Peptidotriazoles on solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. Tornøe CW, Sengeløv H, Meldal M. J. Org. Chem. 2002, 67 (9), 3057–3064.
[4] A strain-promoted [3 + 2] azide−alkyne cycloaddition for covalent modification of biomolecules in living systems. Agard NJ, Prescher JA, Bertozzi CR. J. Am. Chem. Soc. 2004, 126 (46), 15046–15047
[5] In vivo imaging of membrane associated glycans in developing zebrafish. Laughlin ST, Baskin JM, Amacher SL, Bertozzi CR. Science 2008, 320 (5876), 664–667.
[6] Small molecule inhibitors of mucin-type O-glycosylation from a uridine-based library. Hang, HC, Yu, C, Ten Hagen, KG, Tian, E, Winans, KA, Tabak, LA, Bertozzi, Chem Biol. 2004 Jul;11(7):1009-1016.
Links:
The Nobel Prize in Chemistry 2022 (The Royal Swedish Academy of Sciences, Stockholm)
Video: Announcement of the 2022 Nobel Prize in Chemistry (YouTube)
Click Chemistry and Bioorthogonal Chemistry (The Royal Swedish Academy of Sciences)
Sharpless Lab (Scripps Research, La Jolla, CA)
Bertozzi Group (Stanford University, Palo Alto, CA)
NIH Support:
K. Barry Sharpless: National Institute of General Medical Sciences
Carolyn R. Bertozzi: National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences
Dynamic View of Spike Protein Reveals Prime Targets for COVID-19 Treatments
Posted on by Dr. Francis Collins
This striking portrait features the spike protein that crowns SARS-CoV-2, the coronavirus that causes COVID-19. This highly flexible protein has settled here into one of its many possible conformations during the process of docking onto a human cell before infecting it.
This portrait, however, isn’t painted on canvas. It was created on a computer screen from sophisticated 3D simulations of the spike protein in action. The aim was to map its many shape-shifting maneuvers accurately at the atomic level in hopes of detecting exploitable structural vulnerabilities to thwart the virus.
For example, notice the many chain-like structures (green) that adorn the protein’s surface (white). They are sugar molecules called glycans that are thought to shield the spike protein by sweeping away antibodies. Also notice areas (purple) that the simulation identified as the most-attractive targets for antibodies, based on their apparent lack of protection by those glycans.
This work, published recently in the journal PLoS Computational Biology [1], was performed by a German research team that included Mateusz Sikora, Max Planck Institute of Biophysics, Frankfurt. The researchers used a computer application called molecular dynamics (MD) simulation to power up and model the conformational changes in the spike protein on a time scale of a few microseconds. (A microsecond is 0.000001 second.)
The new simulations suggest that glycans act as a dynamic shield on the spike protein. They liken them to windshield wipers on a car. Rather than being fixed in space, those glycans sweep back and forth to protect more of the protein surface than initially meets the eye.
But just as wipers miss spots on a windshield that lie beyond their tips, glycans also miss spots of the protein just beyond their reach. It’s those spots that the researchers suggest might be prime targets on the spike protein that are especially promising for the design of future vaccines and therapeutic antibodies.
This same approach can now be applied to identifying weak spots in the coronavirus’s armor. It also may help researchers understand more fully the implications of newly emerging SARS-CoV-2 variants. The hope is that by capturing this devastating virus and its most critical proteins in action, we can continue to develop and improve upon vaccines and therapeutics.
Reference:
[1] Computational epitope map of SARS-CoV-2 spike protein. Sikora M, von Bülow S, Blanc FEC, Gecht M, Covino R, Hummer G. PLoS Comput Biol. 2021 Apr 1;17(4):e1008790.
Links:
COVID-19 Research (NIH)
Mateusz Sikora (Max Planck Institute of Biophysics, Frankfurt, Germany)
The surprising properties of the coronavirus envelope (Interview with Mateusz Sikora), Scilog, November 16, 2020.
How Mucus Tames Microbes
Posted on by Dr. Francis Collins
Most of us think of mucus as little more than slimy and somewhat yucky stuff that’s easily ignored until you come down with a cold like the one I just had. But, when it comes to our health, there’s much more to mucus than you might think.
Mucus covers the moist surfaces of the human body, including the eyes, nostrils, lungs, and gastrointestinal tract. In fact, the average person makes more than a liter of mucus each day! It houses trillions of microbes and serves as a first line of defense against the subset of those microorganisms that cause infections. For these reasons, NIH-funded researchers, led by Katharina Ribbeck, Massachusetts Institute of Technology, Cambridge, are out to gain a greater understanding of the biology of healthy mucus—and then possibly use that knowledge to develop new therapeutics.
Ribbeck’s team used a scanning electron microscope to take the image of mucus you see above. You’ll notice right away that mucus doesn’t look like simple slime at all. In fact, if you could zoom into this complex web, you’d discover it’s made up of mucin proteins and glycans, which are sugar molecules that resemble bottle brushes.
Ribbeck and her colleagues recently discovered that the glycans in healthy mucus play a long-overlooked role in “taming” bacteria that might make us ill [1]. This work builds on their previous findings that mucus interferes with bacterial behavior, preventing these bugs from attaching to surfaces and communicating with each other [2].
In their new study, published in Nature Microbiology, Ribbeck, lead author Kelsey Wheeler, and their colleagues studied mucus and its interactions with Pseudomonas aeruginosa. This bacterium is a common cause of serious lung infections in people with cystic fibrosis or compromised immune systems.
The researchers found that in the presence of glycans, P. aeruginosa was rendered less harmful and infectious. The bacteria also produced fewer toxins. The findings show that it isn’t just that microbes get trapped in a tangled web within mucus, but rather that glycans have a special ability to moderate the bugs’ behavior. The researchers also have evidence of similar interactions between mucus and other microorganisms, such as those responsible for yeast infections.
The new study highlights an intriguing strategy to tame, rather than kill, bacteria to manage infections. In fact, Ribbeck views mucus and its glycans as a therapeutic gold mine. She hopes to apply what she’s learned to develop artificial mucus as an anti-microbial therapeutic for use inside and outside the body. Not bad for a substance that you might have thought was nothing more than slimy stuff.
References:
[1] Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection. Wheeler KM, Cárcamo-Oyarce G, Turner BS, Dellos-Nolan S, Co JY, Lehoux S, Cummings RD, Wozniak DJ, Ribbeck K. Nat Microbiol. 2019 Oct 14.
[2] Mucins trigger dispersal of Pseudomonas aeruginosa biofilms. Co JY, Cárcamo-Oyarce, Billings N, Wheeler KM, Grindy SC, Holten-Andersen N, Ribbeck K. NPJ Biofilms Microbiomes. 2018 Oct 10;4:23.
Links:
Cystic Fibrosis (National Heart, Lung, and Blood Institute/NIH)
Video: Chemistry in Action—Katharina Ribbeck (YouTube)
Katharina Ribbeck (Massachusetts Institute of Technology, Cambridge)
NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Environmental Health Sciences; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases
