Greg Winter : Bicyclic peptides & chemistry of bicycles

 

Greg Winter studied Natural Sciences at the University of Cambridge.  He then completed his PhD at the LMB, working on the amino acid sequence of tryptophanyl tRNA synthetase from the bacterium Bacillus stearothermophilus. His research career has been based almost entirely at the LMB and the MRC Centre for Protein Engineering (CPE). He became a Programme Leader in 1981, was Joint Head of the PNAC Division from 1994-2006, Deputy Director of the LMB from 2006-2011 and acting Director 2007-2008.  He was also Deputy Director of CPE from 1990 until its closure in 2010.

slide04His main research focus is genetic and protein engineering. In his early research Greg was interested in the idea that all antibodies have the same basic structure, with only small changes making them specific for one target. He pioneered techniques in humanised and human therapeutic antibodies, which led to antibody therapies for cancer and diseases such as rheumatoid arthritis and multiple sclerosis. He has established hugely successful spin out companies including: Cambridge Antibody Technology (acquired by AstraZeneca), Domantis (acquired by GlaxoSmithKline) and Bicycle Therapeutics.

He is a Fellow of Trinity College, Cambridge and has been Master of Trinity since 2012. He was elected a member of the European Molecular Biology Organisation in 1987, a Fellow of the Royal Society in 1990 and Fellow of the Academy of Medical Sciences in 2006, as well as being a Fellow or Honorary Fellow of many other professional organisations. He has been awarded numerous prizes and medals, including the 2018 Nobel Prize for Chemistry.  He received a Knighthood for services to Molecular Biology in 2004.

bicycle-1Natural peptides are flexible molecules; not only does this limit their binding affinity but it facilitates their cleavage by proteases, and it has compromised their development as pharmaceuticals. Our research has aimed to create a new generation of therapeutic agents, “bicycles”, based on highly constrained peptides with a bicyclic structure and a chemical core.

 

We undertook selections to make bicyclic peptides against various targets. In our early research, we described a bicyclic inhibitor of kallikrein. This peptide, PK15, was derived from a large bicyclic random peptide repertoire displayed on filamentous bacteriophage that had been selected against kallikrein. Further studies of PK15 suggested that the structure of the peptide backbone in PK15 must be rather constrained and showed that the amino acid loops of PK15 are constrained in an open “butterfly” configuration in solution.

bicycle-binding-sites More recently, we made bicyclic peptides against UK18 bicyclic peptide, an inhibitor of human urokinase-type plasminogen activator (uPA) and M21, a ligand for a cryptic epitope of human tumour necrosis factor (TNF). Analysis by X-ray crystallography of the structure of these peptides in complex with their targets revealed that bicyclic peptides have the ability to mimic both antibody and chemical ligands and confirms that bicyclic peptides may be able to combine features of both major classes of pharmaceuticals.

figurex_hydrophobicity2In summary, bicycles can be selected with high affinity and specificity to targets, are highly resistant to attack by proteases and appear to have constrained structures with the two loops in an open “butterfly” configuration. Key patents have been filed, the methodologies for creating bicycles improved and the know-how successfully spun out into the start-up company Bicycle Therapeutics. Bicycles seem able to mimic the properties of both antibodies and small chemical ligands, and may prove very suitable targeting entities for bringing chemical toxins to tumour cells. Such bicycle drug conjugates (BDCs) are currently in development as cancer therapeutics by Bicycle Therapeutics for clinical application.

Quantum dots can spit out clone-like photons

 

In the global quest to develop practical computing and communications devices based on the principles of quantum physics, one potentially useful component has proved elusive: a source of individual particles of light with perfectly constant, predictable, and steady characteristics. Now, researchers at MIT and in Switzerland say they have made major steps toward such a single photon source.

The study, which involves using a family of materials known as perovskites to make light-emitting particles called quantum dots, appears today in the journal Science. The paper is by MIT graduate student in chemistry Hendrik Utzat, professor of chemistry Moungi Bawendi, and nine others at MIT and at ETH in Zurich, Switzerland.

The ability to produce individual photons with precisely known and persistent properties, including a wavelength, or color, that does not fluctuate at all, could be useful for many kinds of proposed quantum devices. Because each photon would be indistinguishable from the others in terms of its quantum-mechanical properties, it could be possible, for example, to delay one of them and then get the pair to interact with each other, in a phenomenon called interference.

"This quantum interference between different indistinguishable single photons is the basis of many optical quantum information technologies using single photons as information carriers," Utzat explains. "But it only works if the photons are coherent, meaning they preserve their quantum states for a sufficiently long time."

Many researchers have tried to produce sources that could emit such coherent single photons, but all have had limitations. Random fluctuations in the materials surrounding these emitters tend to change the properties of the photons in unpredictable ways, destroying their coherence. Finding emitter materials that maintain coherence and are also bright and stable is "fundamentally challenging," Utzat says. That's because not only the surroundings but even the materials themselves "essentially provide a fluctuating bath that randomly interacts with the electronically excited quantum state and washes out the coherence," he says.

"Without having a source of coherent single photons, you can't use any of these quantum effects that are the foundation of optical quantum information manipulation," says Bawendi, who is the Lester Wolfe Professor of Chemistry. Another important quantum effect that can be harnessed by having coherent photons, he says, is entanglement, in which two photons essentially behave as if they were one, sharing all their properties.

Previous chemically-made colloidal quantum dot materials had impractically short coherence times, but this team found that making the quantum dots from perovskites, a family of materials defined by their crystal structure, produced coherence levels that were more than a thousand times better than previous versions. The coherence properties of these colloidal perovskite quantum dots are now approaching the levels of established emitters, such as atom-like defects in diamond or quantum dots grown by physicists using gas-phase beam epitaxy.

One of the big advantages of perovskites, they found, was that they emit photons very quickly after being stimulated by a laser beam. This high speed could be a crucial characteristic for potential quantum computing applications. They also have very little interaction with their surroundings, greatly improving their coherence properties and stability.

Such coherent photons could also be used for quantum-encrypted communications applications, Bawendi says. A particular kind of entanglement, called polarization entanglement, can be the basis for secure quantum communications that defies attempts at interception.

Now that the team has found these promising properties, the next step is to work on optimizing and improving their performance in order to make them scalable and practical. For one thing, they need to achieve 100 percent indistinguishability in the photons produced. So far, they have reached 20 percent, "which is already very remarkable," Utzat says, already comparable to the coherences reached by other materials, such as atom-like fluorescent defects in diamond, that are already established systems and have been worked on much longer.

"Perovskite quantum dots still have a long way to go until they become applicable in real applications," he says, "but this is a new materials system available for quantum photonics that can now be optimized and potentially integrated with devices."

It's a new phenomenon and will require much work to develop to a practical level, the researchers say. "Our study is very fundamental," Bawendi notes. "However, it's a big step toward developing a new material platform that is promising."

The work was supported by the U.S. Department of Energy, the National Science Foundation, and the Swiss Federal Commission for Technology and Innovation.

Ultra-lightweight ceramic material withstands extreme temperatures

 

UCLA researchers and collaborators at eight other research institutions have created an extremely light, very durable ceramic aerogel. The material could be used for applications like insulating spacecraft because it can withstand the intense heat and severe temperature changes that space missions endure.

Ceramic aerogels have been used to insulate industrial equipment since the 1990s, and they have been used to insulate scientific equipment on NASA's Mars rover missions. But the new version is much more durable after exposure to extreme heat and repeated temperature spikes, and much lighter. Its unique atomic composition and microscopic structure also make it unusually elastic.

When it's heated, the material contracts rather than expanding like other ceramics do. It also contracts perpendicularly to the direction that it's compressed -- imagine pressing a tennis ball on a table and having the center of the ball move inward rather than expanding out -- the opposite of how most materials react when compressed. As a result, the material is far more flexible and less brittle than current state-of-the-art ceramic aerogels: It can be compressed to 5 percent of its original volume and fully recover, while other existing aerogels can be compressed to only about 20 percent and then fully recover.

The research, which was published today in Science, was led by Xiangfeng Duan, a UCLA professor of chemistry and biochemistry; Yu Huang, a UCLA professor of materials science and engineering; and Hui Li of Harbin Institute of Technology, China. The study's first authors are Xiang Xu, a visiting postdoctoral fellow in chemistry at UCLA from Harbin Institute of Technology; Qiangqiang Zhang of Lanzhou University; and Menglong Hao of UC Berkeley and Southeast University.

Other members of the research team were from UC Berkeley; Purdue University; Lawrence Berkeley National Laboratory; Hunan University, China; Lanzhou University, China; and King Saud University, Saudi Arabia.

Despite the fact that more than 99 percent of their volume is air, aerogels are solid and structurally very strong for their weight. They can be made from many types of materials, including ceramics, carbon or metal oxides. Compared with other insulators, ceramic-based aerogels are superior in blocking extreme temperatures, and they have ultralow density and are highly resistant to fire and corrosion -- all qualities that lend themselves well to reusable spacecraft.

But current ceramic aerogels are highly brittle and tend to fracture after repeated exposure to extreme heat and dramatic temperature swings, both of which are common in space travel.

The new material is made of thin layers of boron nitride, a ceramic, with atoms that are connected in hexagon patterns, like chicken wire.

In the UCLA-led research, it withstood conditions that would typically fracture other aerogels. It stood up to hundreds of exposures to sudden and extreme temperature spikes when the engineers raised and lowered the temperature in a testing container between minus 198 degrees Celsius and 900 degrees above zero over just a few seconds. In another test, it lost less than 1 percent of its mechanical strength after being stored for one week at 1,400 degrees Celsius.

"The key to the durability of our new ceramic aerogel is its unique architecture," Duan said. "Its innate flexibility helps it take the pounding from extreme heat and temperature shocks that would cause other ceramic aerogels to fail."

Ordinary ceramic materials usually expand when heated and contract when they are cooled. Over time, those repeated temperature changes can lead those materials to fracture and ultimately fail. The new aerogel was designed to be more durable by doing just the opposite -- it contracts rather than expanding when heated.

In addition, the aerogel's ability to contract perpendicularly to the direction that it's being compressed -- like the tennis ball example -- help it survive repeated and rapid temperature changes. (That property is known as a negative Poisson's ratio.) It also has interior "walls" that are reinforced with a double-pane structure, which cuts down the material's weight while increasing its insulating abilities.

Duan said the process researchers developed to make the new aerogel also could be adapted to make other ultra-lightweight materials.

"Those materials could be useful for thermal insulation in spacecraft, automobiles or other specialized equipment," he said. "They could also be useful for thermal energy storage, catalysis or filtration."

The research was partly supported by grants from the National Science Foundation.