Molecular Constructor
Nanoconstructor for the creation of drugs
Biochemists have created a platform for coating (modifying) the surfaces of nano- and microparticles with structures made of biomolecules. These designs can have drug and recognition parts and be used for targeted delivery of drugs to the tumor. The work was published in the journal ACS Applied Materials & Interfaces. The development was carried out by an international group of scientists, which includes researchers from MIPT, the M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, MEPhI, I. M. Sechenov Moscow State Medical University and Macquarie University (Australia). The results obtained are briefly reported in the MIPT press release.
"Magic Bullet": deliver and cure
The concept of the "magic bullet" was formulated by the Nobel Prize winner in Physiology and Medicine Paul Ehrlich at the turn of the nineteenth and twentieth centuries. This is a construction consisting of two parts: a drug and a target–recognizing agent - a molecule that can "recognize" another molecule in the body (the target). The target is most often the receptors on the surface of the "problem" cell, with which the agent recognizes the cell. Such a universal system can be used both for therapy (treatment) and for the diagnosis of a disease or simultaneous diagnosis and therapy (theranostics).
To create such a system, therapeutic and diagnostic (recognizing) blocks are needed, as well as a powerful "molecular glue" that can connect them. Proteins that can bind tightly to each other, forming a stable complex, can act as a "glue".
One of the most stable complexes is a pair of small bacterial proteins – barnase and barstar, their binding constant is about 10-14 M–1. The greater the binding constant, the stronger the molecules are connected to each other. For comparison, protein complexes of the antigen-antibody type, on which the work of our immune system is based, have binding constants in the range of 10 8-10 11 M–1. On the basis of barnase and barstar, separate blocks can be created by attaching, for example, a therapeutic agent (antibodies, drugs, fluorescent molecules, etc.) to barnase, and a guiding agent to barstar. Then, when the blocks are combined, a bifunctional compound is formed, which has both a guiding and a medicinal effect, with the help of which directed delivery of the drug is possible.
Thus, by "sewing" various therapeutic and recognizing molecules to barnaza and barstar, we can obtain various theranostic means based on the same principle. Similar molecular structures (not necessarily the same) can be placed on a single carrier – a nano- or microparticle. Particles can have additional properties: for example, they can fluoresce or break down under the influence of radiation and then destroy harmful (for example, cancer) cells. In addition, dozens of molecular structures can be placed on the surface of the particles, which can increase the therapeutic effect.
Nanoconstructor
The idea of delivering medicines based on nano- and microparticles is actively developing in scientific laboratories. The authors of the study designed and studied the properties of a teranostic agent based on nanoparticles and the barnaza-barstar protein complex.
"Most of the currently existing methods of chemical conjugation of nanoparticles with biomolecules have a number of serious problems. These are undirected attachment and low density of attached molecules, spatial difficulties in binding to receptors on the cell surface, a long modification time, and a number of others. The method developed by us based on the barnaza-barstar protein module does not change the spatial structure of the recognizing molecules, has high specificity and fast kinetics of formation: it takes several minutes to connect all the blocks," says the first author of the article, an employee of the MIPT nanobiotechnology laboratory, senior researcher at the Laboratory of Molecular Immunology of the M. M. Shemyakin and Yu. A. IBH. Ovchinnikova RAS Victoria Shipunova.
The scientists used particles coated with silicon dioxide SiO 2 to attach to the molecular complex.
The main purpose of the structures described in this paper is cancer cells that can be recognized using the HER2 cancer marker on their surface. HER2 is a protein responsible for cell growth and division. It is also present in healthy cells, but in cancer cells HER2 is in excess (overexpressed), which, among other things, allows the cancer cell to divide and grow uncontrollably. As a HER2–recognizing agent, scientists chose a molecule from the DARPins class (DARPins – Designed Ankyrin Repeat Proteins - proteins with ankyrin repeats). These are small and very stable proteins capable of selectively binding to the target molecule.
In addition to the darpin recognition molecule, the design must also contain a molecule capable of connecting to the surface of a nano- or microparticle, that is, with silicon dioxide. Scientists used for this purpose a SiO2-binding peptide obtained by genetic engineering methods. As a result, the final design looks like this: a nano- or microparticle coated with silicon dioxide is connected to the barnase-darpin block by means of a SiO2-binding peptide with a barstar (Figure 1). It is important to note that each of these elements can be changed or even replaced, affecting the properties of the entire structure. It turned out to be a kind of molecular constructor for the creation of new drugs.
Figure 1. Scheme of formation of a nanoconstruction based on nanoparticles and the barnaza-barstar protein complex
Figure 2. Scheme of operation of theranostic constructions
Thus, scientists have managed to create a universal molecular constructor that makes it easy to combine different molecules for the treatment and diagnosis of diseases, preserving their spatial structure and properties.
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