A large number of the most important proteins of modern medicine and science are insoluble. These comprise a host of signalling proteins and protein hormones, and all of the receptors embedded in the cell membranes, which are directed at approximately 60 percent of the active ingredients presently utilized in medicines. When the concentration of these proteins crosses some given level, they will form clumps and become useless.
This aggregation renders synthesis of these molecules in lab impossible. Since specialised production with specialised synthesing robots always needs more than a single fragment to be conjugated into a full protein, a single poorly soluble fragment of protein is usually sufficient to inhibit production. The reason is that the current techniques employed by chemists to assemble protein fragments merely perform successfully when the fragments exist in solution and in very high concentrations.
A team of researchers, headed by Jeffrey Bode, professor at the Laboratory of Organic Chemistry at ETH Zurich has now discovered how to couple even the poorly soluble portions of proteins into functional proteins. In order to do this, they utilized special properties of a chemical compound comprising an element named boron.
The slow carbon chemistry has a concentration constraint.
The only major difference between the ETH technique and the traditional strategies is in the rate of the coupling reaction. Unlike in biochemistry, which occurs extremely fast in cells of living organisms, through enzymes, reactions such as these typically need to be carried out at unnatural concentrations within the laboratory. The reason behind this is that the slower the reaction is taking place, the greater the concentration of the reacting substances should be so that the reaction processes take place as intended.
The novel coupling technique invented by the team of Bode is approximately 1000 times faster and thus was also applicable in 1000 times lower concentrations.
Boron opens up new opportunities bio-chemistry
The ETH chemists hastened the reaction by including Boron atoms to the carbon-based molecules. These are not found in natural molecules.
In several of its properties, the metalloid boron behaves in a somewhat different way. On bonding with metals, it forms very tough and heat-resistant metal alloys. Alternatively, it is capable of bonding with the nonmetals carbon, oxygen or nitrogen in the lab to form molecules that tend to have bizarre reaction characteristics. In 2010, Akira Suzuki, a Japanese researcher and Richard Heck, an American researcher, won the Nobel Prize in Chemistry due to the development of boron-based coupling reactions to enable laboratory synthesis of natural substances.
According to Bode, “We reach an ultimate limit of reaction rate with purely carbon based systems. It is further expansion into previously untapped boron based reagents that places us in a space where even the most recalcitrant reactions that bring large biological molecules together can occur in a very brief time.”
Protective acids: a rocky road
As shown by Bode and colleagues in 2012, this was the first study to demonstrate that it was possible to add an element of a hitherto unexplored chemical group to proteins fragments and do so with great speed and stability. Nevertheless, this compound was not stable with strong acids hence could not be utilized in automated synthesis.
To endure the tough environment that was applied to the sensitive boron compound in normal laboratory robots, the compound would require protection in the form of a chemical packaging, but this was easier said than done. The researchers experimented with a number of strategies in four years to little effect.
The discovery was made by mistake and eventually, the discovery occurred when a doctoral student tried an experimental method that the team had indeed thought was ineffective. The resulting protective compound binds to the boron group on three sides, therefore, being unable to be terminated in the acids in protein production.
According to Bode, such fundamental research, in which there is no assurance of success, is feasible only due to the unrestricted funds provided by the Swiss National Science Foundation and ETH.
Inorganic amino acids and cancer treatment
The ETH method implies that new peptide and protein drugs or drugs of medical interest to cure cancer that are prone to clumping, can now be produced via the usual laboratory protocols.
Moreover, special amino acids that are not natural can also be incorporated in the location of choice on the poorly soluble proteins. As an example, the chemists can functionalized these building blocks in a protein in a specific way in case they wish to attach it to an active substance on a particular location. Some of the applications of antibody-drug conjugates prepared through this method include cancer treatment procedures that do not damage normal tissues.
The way in which the method will be applied to clinical practice is not yet clear. In 2020 Bode co-founded the ETH spin-out Bright Peak Therapeutics, which applications the technologies invented in his lab to build immunotherapies to fight cancer. A therapeutic agent has already entered clinical trials and the new method based on boron may assist in increasing the size of the product pipeline of the spin-off.
Use of Boron in Proteins to Create New Treatments to Cure Cancer: Study added by Arun Kumar N on
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