WO2023068958A1 - Systèmes supramoléculaires à base de nanostructures dynamiques à organisation automatique possédant des propriétés antivirales - Google Patents

Systèmes supramoléculaires à base de nanostructures dynamiques à organisation automatique possédant des propriétés antivirales Download PDF

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WO2023068958A1
WO2023068958A1 PCT/RU2021/000447 RU2021000447W WO2023068958A1 WO 2023068958 A1 WO2023068958 A1 WO 2023068958A1 RU 2021000447 W RU2021000447 W RU 2021000447W WO 2023068958 A1 WO2023068958 A1 WO 2023068958A1
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supramolecular
combinatorial
carboxylated
binding
succinylated
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Russian (ru)
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Борис Славинович ФАРБЕР
Артур Викторович МАРТЫНОВ
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Борис Славинович ФАРБЕР
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis

Definitions

  • the present invention relates to supramolecular nanoparticles produced using combinatorial chemical building blocks self-assembling into nanoparticles, acting on the basis of molecular recognition, and methods for controlling the size of the resulting nanoparticles.
  • the invention also includes methods for using supramolecular structures to treat viral infections.
  • Supramolecular chemistry is the field of chemistry with respect to chemical systems composed of a discrete number of molecules.
  • the forces responsible for the spatial organization of a system range from weak intermolecular forces, electrostatic charge, or strong covalent bonding hydrogen bonds, provided that the electronic bond strength remains small relative to the energy parameters of the component.
  • supramolecular chemistry considers weaker and reversible non-covalent interactions between molecules. These forces include the formation of hydrogen bonds, coordination bonds of metals, hydrophobic forces of van der Waals interactions, pi-pi interactions and electrostatic effects.
  • Important advanced concepts in supramolecular chemistry include molecular self-assembly, molecular folding, molecular recognition, host-guest chemistry, mechanically interlocked molecular architectures, and dynamic covalent chemistry.
  • the study of non-covalent interactions is critical to understanding the many biological processes that depend on these forces for structure and function.
  • Biological systems are often the inspiration for supramolecular research.
  • new supramolecular structures are associated with new intermolecular relationships in many ways that are complementary to the chemistry of the molecular structures themselves.
  • atoms play a critical role in the paradigms of chemistry, the molecular structure of a chemical is still central to the chemistry of many important technological and biological materials.
  • the "intelligent glue" of molecular structure is a covalent bond that binds atoms and forms the stereochemistry of atoms in space.
  • the covalent chemical bond paradigm provides many rules governing the structure, dynamics, physical characteristics, and chemical transformations of molecules.
  • the level of atomic structure is not a sufficient basis for a sufficient understanding of aspects of chemistry where molecular aspects predominate.
  • the level of molecular structure is insufficient to understand aspects of chemistry where supramolecular aspects dominate.
  • the chemistry of intermolecular bonds bind together in assemblies we may call supermolecules.
  • non-covalent intermolecular bonds are more far varied and complex than covalent intramolecular bonds in the structures known as molecules.
  • Supramolecular systems can be held together by much weaker forces than the atoms in a molecule.
  • the forces that hold multiple molecules together as supramolecular structures can include dispersion forces, hydrogen bonds, and hydrophobic bonds.
  • supramolecular systems can participate in supervalence states, in which supramolecular complexes containing many individual molecules are stable in many combinations with a common conformation at both ends of the molecule and supramolecular levels due to the possible summation of various combinations of a large number of weak intermolecular interactions.
  • Remarkable examples of such models are the micelle and the DNA double helix.
  • supramolecular chemistry is concerned with the structure and dynamics of a small molecule (called a guest) that is non-covalently bound to a larger molecule (called a host or host).
  • a guest small molecule
  • a host larger molecule
  • the concept of guest/host has the highest chemical informational value when the distinction between guest and host is clear.
  • the guest is a molecule that is relatively small compared to the host, and the host can either be one large molecule or an assembly of molecules that behave as one.
  • the host provides a cage that completely surrounds the guest (guest/cage) or the host provides a cavity (guest/cavity) that partially surrounds the guest.
  • guest/cavity cavities
  • one monomer in micelles composed of surfactant monomers, one monomer can be considered as a guest in the host in its own supramolecular assembly.
  • a molecule that is not a surfactant monomer is a pure guest in the micelle of the surfactant assembly.
  • An important term for the formation of an intermolecular bond between a guest and a host is "complexation" - a term that retains the idea of a chemically appropriate "looseness" based on non-covalent bonds between molecules.
  • the host is a partner of the guest/host complex of design properties and whose structural changes are determined by the type of guests who will be associated in the complex.
  • chemistry or physical properties can be more or less studied.
  • These concepts are derived from enzyme chemistry paradigms and provide a familiar and useful working framework for discussing supramolecular chemistry.
  • the guest/host complex can be considered as a supermolecule or a supramolecular assembly depending on the complexity of the supramolecular structure under discussion.
  • Supramolecular chemistry is explained in a variety of ways, such as the chemistry of molecular assemblies and intermolecular bonds, the chemistry outside the molecule, and the chemistry of the non-covalent bond. It is important that each definition has its limitations and exceptions. Indeed, supramolecular chemistry can be defined as the chemistry of molecular assemblies from a molecule in a solvent molecular cell to a composition of molecular assemblies (consisting of proteins, lipids, DNA, RNA, etc.) that represent the enormous chemical complexity of a living cell.
  • two molecules can be considered as bonding, regardless of the nature of the bond and due to the proximity of their atoms to each other.
  • a molecule that is contained as a guest inside the host fullerene has a certain connection with the inner cell of the fullerene.
  • a molecule that is held as a guest in the host cavity such as cyclodextrin or cavitand, has a specific interaction with the atoms of the host cavity.
  • a molecule that is contained as a guest in a crystal and is surrounded by molecules of the crystalline host has certain interactions with the molecules of the crystal surrounding it.
  • the guest molecule that is intercalated into the DNA double helix of the host is chemically bonded to a small set of specific bases that are found in its vicinity.
  • Drug nanoparticles are typically particles comprising drug substances such as small drug molecules, peptides, proteins and nucleic acids, as well as components that are assembled with other drug substances such as lipids and polymers. Such nanoparticles may have an increased anti-cancer effect compared to the same but free drugs. This is due to a more specific orientation and tropism to tumor tissues due to improved pharmacokinetics and pharmacodynamics, as well as more active intracellular delivery. These properties depend on the size and properties of the surface, including the specific orientation of the ligands in the nanoparticle. A limited number of such nanoparticle-based systems have reached clinical use, and for starters information is becoming available to understand some of the issues involved in the movement of these experimental systems in the human body.
  • nanoparticle types include gold nanoshells (Loo et al., Technol. Cancer Res. Trea, vol. 3, p. 33, 2004), quantum dots (Gao et al., Nat. Biotechnol., vol. 22, p 969, 2004; Nie et al., Annu. Rev. Biomed. Eng., vol. 9, p. 257, 2007), superparamagnetic nanoparticles (Jun et al., Angew. Chem., vol. 120, p 5200, 20080; Jun et al., Angew. Chem. Int. Ed., vol. 47, p. 5122, 2008).
  • Nanoparticles bearing specific target ligands are used for in vivo imaging of cancer, and drug molecules can be packaged in polymer-based nanoparticles or liposomes (Heath et al., Annu. Rev. Med., vol. 59, p. 251, 2008 ; Torchilin et al., Nat. Rev. Drug Discov., vol. 4, p. 145, 2005) for controlled drug release (Napier et al., Poly. Rev., vol. 47, p. 321, 2007; Gratton et al., Acc. Chem. Res., vol. 41, p. 1685, 2008).
  • Positively charged nanoparticles have been used as a non-viral delivery system in vitro and in vivo for genetic manipulation and genetic programming (Davis et al., Nat. Rev. Drug Discov., vol. 7, p. 771, 2008; Green et al. ., Acc. Chem. Res., vol. 41, p. 749, 2008; Pack et al., Nat. Rev. Drug Discov., vol. 4, p. 581, 2005).
  • Nanostructures based on noble metals with unique photophysical properties with a focus on photothermal agents for cancer therapy (Anderson et al., Science, vol. 220, p. 524, 1983; Jain et al., Acc Chem Res, vol. 41, p. 1578, 2008; An et aL, Nano Today, vol. 4, p. 359, 2009; Lal et al., Acc Chem Res, vol. 41, p. 1842, 2008).
  • Changes in the photothermal properties of nanostructures in terms of their size and shape (Lal et aL, Acc Chem Res, vol. 41, p. 1842, 2008; Skrabalak et al., Acc Chem Res, vol.
  • gold (Au) based photothermal nanostructures are well known (Lapotko et al., Laser Surg Medi, vol. 38, p. 631, 2006; Huang et al., Lasers Med Sci, vol. 23, p. 217, 2008), nanoshells (Gobin et al., Nano Lett, vol. 7, p. 1929, 2007; Hu et al., J Am Chem Soc, vol. 131, p. 14186, 2009; Kim et al., Angewandte Chemie -Intemational Edition, vol. 45, p. 7754, 2006), nanorods (Dickerson et al., Cancer Letters, vol.
  • Au-containing nanostructures are an improvement over nanoparticles based on organic dyes and photothermal agents with low light absorption and the unwanted side effect of photobleaching (Huang et aL, Lasers Med Sci, vol. 23, p. 217, 2008).
  • nanostructured agents require short wavelength light (in the range of tens to hundreds of nanometers) to kill cancer cells.
  • known nanostructured substances are not well excreted from the liver, spleen and kidneys), and these cumulative properties are undesirable for medical use (Mitragotri et aL, Nat Mater, vol. 8, p. 15, 2009; Choi et aL , Nat Biotechnol, vol.25, p.1165, 2007; Nel et aL, Nat Mater, vol.8, p.543, 2009).
  • non-viral gene therapy delivery methods that can (i) transfer and protect genetic material, such as DNA and siRNA, and (b) deliver gene therapy to selected cells and cells of various tissue types (Kim et al. Nat Rev Genet, vol. 8, p.p. 173-184, 2007). Improvements in non-viral gene delivery vehicles have been made (Glover et al., Nat Rev Genet, vol. 6, pp. 299-310, 2005; Rosi et al., Chem. Rev., vol. 105, pp. 1547-1562, 2005).
  • Prior art non-viral gene delivery systems include (Niidome et al., Gene Ther., vol. 9, p.
  • Prior art nanoparticle-based gene delivery vehicles include (Liang et al., Proc Natl Acad Sci USA, vol. 102, pp. 11173-11178, 2005; Kumar et al., Chem. Commun., pp.
  • Supramolecular nanoparticles may include: a combination of nanostructures selected from the group consisting of combinatorial carboxylated cobalamins obtained from the first combinatorial synthesis; combinatorial carboxylated dipyridamoles obtained from the second combinatorial synthesis; polypeptides from basic amino acids obtained from the third combinatorial synthesis, as well as any combination thereof.
  • the supramolecular nanoparticle may have antiviral properties, and may further include dynamic self-assembling soluble nanostructures, and these nanostructures may further include a plurality of binding components; many organic nuclei; and many terminal components.
  • the supramolecular nanoparticles may have one of the binder components, which may further comprise combinatorial carboxylated cobalamins having a number of binding regions, and the organic cores may further contain combinatorial carboxylated dipyridamoles, having at least one binding element, adapted for binding with combinatorial carboxylated cobalamins, and organic cores may additionally include mechanical structures of dynamic self-organizing soluble nanostructures, also combinatorial carboxylated cobalamins, which are associated with combinatorial carboxylated dipyridamoles and may additionally include primary inclusion complexes.
  • the supramolecular nanoparticle may contain termination components, each of which may have at least one terminating element, and may also additionally contain secondary inclusion complexes.
  • Supramolecular nanoparticles may contain polypeptides from basic amino acids, may also additionally contain carboxylated oligopeptides from basic amino acids, such as lysine, histidine, arginine, derivatized lysine, derivatized histidine, derivatized arginine, acylated lysine, acylated histidine, acylated arginine, and any combination thereof.
  • a supramolecular nanoparticle may have a plurality of terminating components that may occupy the remaining binding sites of a plurality of binding components, and when the plurality of terminating components may be equivalent to the number of binding regions of a plurality of binding components, after which further binding of the binding components stops, also supramolecular nanoparticles may additionally contain discrete nanoparticles on basis of dynamic self-organizing soluble nanostructures.
  • the supramolecular nanoparticles may contain combinatorial carboxylated cobalamins, which may be a mixture of succinylated cyanocobalamins.
  • Supramolecular nanoparticles may contain combinatorial carboxylated cobalamins, which may be represented by a mixture of succinylated methyl cobalamins.
  • Supramolecular nanoparticles may contain combinatorial carboxylated cobalamins, which may be a mixture of succinylated hydroxycobolamines.
  • Supramolecular nanoparticles can contain combinatorial carboxylated cobalamins, which can be represented by a mixture of succinylated cobalamins.
  • the supramolecular nanoparticles may contain combinatorial carboxylated cobalamins, which may be selected from the group consisting of a mixture of succinylated hydroxycobolamines, a mixture of succinylated cobamides, a mixture of succinylated hydroxycobalamins, a mixture of succinylated methylcobalamins, a mixture of succinylated cyanocobolamins, and any combinations thereof.
  • the supramolecular nanoparticles may contain at least one of the organic cores, which may additionally contain at least one element based on the photodynamic component represented by the supramolecular combinatorial carboxylated riboflavin.
  • the supramolecular nanoparticles may contain the supramolecular combinatorial carboxylated riboflavin as the supramolecular combinatorial succinylated riboflavin.
  • the supramolecular nanoparticles may contain the supramolecular combinatorial carboxylated riboflavin as a supramolecular combinatorial succinylated flavin mononucleotide.
  • the supramolecular nanoparticles may contain a supramolecular combinatorial carboxylated riboflavin, presented as a supramolecular combinatorial succinylated flavin dinucleotide.
  • the supramolecular nanoparticles may contain combinatorial carboxylated dipyridamole as supramolecular succinylated combinatorial dipyridamole.
  • Supramolecular nanoparticles may contain combinatorial carboxylated dipyridamoles, which are supramolecular maleylated combinatorial dipyridamoles.
  • Supramolecular nanoparticles may contain combinatorial carboxylated dipyridamoles, which are supramolecular carboxymethylated combinatorial dipyridamoles.
  • the supramolecular nanoparticles may contain carboxylated basic amino acids such as succinylated lysine, succinylated histidine, succinylated arginine, or any combination thereof.
  • the supramolecular nanoparticles may contain carboxylated basic amino acids such as maleylated lysine, maleylated histidine, maleylated arginine, in any combination thereof.
  • Supramolecular nanoparticles may contain carboxylated basic amino acids, including carboxymethylated lysine, carboxymethylated histidine, carboxymethylated arginine, in any combination.
  • the supramolecular nanoparticles may contain carboxylated basic amino acids, including carboxymethylated lysine, carboxymethylated histidine, carboxymethylated arginine, succinylated lysine, succinylated histidine, succinylated arginine, maleylated lysine, maleylated histidine, maleylated arginine, and any combination thereof.
  • carboxylated basic amino acids including carboxymethylated lysine, carboxymethylated histidine, carboxymethylated arginine, succinylated lysine, succinylated histidine, succinylated arginine, maleylated lysine, maleylated histidine, maleylated arginine, and any combination thereof.
  • the supramolecular nanoparticles may contain a plurality of terminating components, which may consist of at least one of the following: polyethylene glycol, polymer, polypeptide, oligosaccharide, and any combination thereof.
  • the supramolecular nanoparticles may contain organic cores consisting of at least one organic core based on a dendrimer, branched polyethyleneimine, linear polyethyleneimine, polylysine, polylactide, polylactide-co-glycoside, polyanhydride, poly-e-caprolactone, A polymethyl methacrylate, poly (N-isopropyl acrylamide), a polypeptide, and any combination thereof.
  • Supramolecular nanoparticles may contain at least one of a variety of binding components, which may additionally contain a combinatorial carboxylated derivative of the main oligopeptide KKRKRKRKR.
  • the supramolecular nanoparticles may contain combinatorial carboxylated derivatives of the basic oligopeptide KKRKRKRKR, which can be succinylated derivatives, where from 1 to 9 free residues of the amino groups of the basic oligopeptide KKRKRKRKR are succinylated.
  • Supramolecular nanoparticles may contain combinatorial carboxylated derivatives of the main oligopeptide KKRKRKRKR, which may be maleylated derivatives, where from 1 to 9 free residues of the amino groups of the main oligopeptide KKRKRKRKR, which may be maleylated derivatives, where from 1 to 9 free residues of the amino groups of the main oligopeptide KKRKRKRKR, which may be maleylated derivatives, where from 1 to 9 free residues of the amino groups of the main
  • the supramolecular nanoparticles may contain combinatorial carboxylated derivatives of the basic oligopeptide KKRKRKRKR, which can be carboxymethylated derivatives, where from 1 to 9 free residues of the amino groups of the basic oligopeptide KKRKRKRKR are carboxymethylated.
  • the supramolecular nanoparticles may contain combinatorial carboxylated derivatives of the basic oligopeptides KKRKRKRKR, which can be combinatorial mixtures of derivatives obtained by succinylation, maleylation and carboxymethylation from 1 to 9 from the free residues of the amino groups of the basic oligopeptide KKRKRKRKR.
  • Supramolecular nanoparticles may contain a binding component, which is a poly-L-lysine.
  • FIG. Figure 1 shows the structures of a soluble self-assembling nanoparticle, dynamic combinatorial cobalamide as a core, dynamic combinatorial dipyridamole as a structural component, dynamic combinatorial derivatives of basic oligopeptides and amino acids as a binding component.
  • FIG. 2 shows a self-organizing dynamic combinatorial derivative of dipyridamole and the principles of its synthesis.
  • FIG. 3 shows the basis of the principle of molecular recognition between different substances based on nucleotide-like structures.
  • FIG. Figure 5 shows the structure of dynamic self-organizing combinatorial derivatives of cyanocobalamin.
  • FIG. Figure 6 shows the HPLC chromatogram of the starting cyanocobalamin under the following chromatographic conditions: gradient separation using buffer A, which contains 0.1 M perchloric acid with 1 M lithium perchlorate, and buffer B, which contains acetonitrile in a gradient (from 5% to 100%) on chromatograph Milichrome A-02 with a prontosil-18 column.
  • FIG. 7 shows an HPLC chromatogram of a combinatorial cyanocobalamin derivative with 128 derivatives under the following chromatographic conditions: gradient separation using buffer A, which contains 0.1 M perchloric acid with 1 M lithium perchlorate, and buffer B, which contains acetonitrile in a gradient (from 5% to 100%) on a Milichrome A-02 chromatograph with a prontosil-18 column.
  • FIG. Figure 8 shows the scheme for the synthesis of a combinatorial derivative of dipyridamole (IV), which includes a combinatorial reaction of dipyridamole (I) with two modifiers (P, III).
  • FIG. 9 is a schematic thin layer chromatogram of a combinatorial dipyridamole derivative (IV), starting dipyridamole (I), fully acylated dipyridamole (lb), and fully succinylated dipyridamole (1c).
  • FIG. 10 shows the result of HPLC analysis of the original KKRKRKRKR peptide.
  • a wavelength of 280 nm with one absorption band is used.
  • FIG. 11 is an HPLC chromatogram of a combinatorial peptide derivative KKRKRKRKR.
  • the peaks of the chromatogram of the combinatorial derivative of the peptide KKRKRKRKR are shifted to the expected more hydrophilic region, while remaining extended, this peak is further divided into 3 bands.
  • FIG. 12 shows the HPLC chromatogram of the original KKRKSTRKR peptide.
  • the original peptide when using a detector in the region of 280 nm, gives one absorption band.
  • FIG. 13 is the result of HPLC analysis of the combinatorial peptide derivative KKRKSTRKR, its chromatogram contains a characteristic triple peak.
  • embodiments of the present invention relate to supramolecular structures, also referred to as supramolecular nanoparticles (SNPs), that can be generated using molecular building block recognition properties based on a dynamic quasi-living self-assembly system.
  • Embodiments of the invention also include methods for obtaining supramolecular structures using molecular recognition and using methods for controlling the size of the resulting nanoparticles.
  • Embodiments of the invention also include methods for using supramolecular structures to treat viral infections.
  • a supramolecular nanoparticle includes: a) a plurality of binders, where each binder has a plurality of binding regions, and wherein the plurality of binding regions comprise combinatorial carboxylated cobalamins; b) a plurality of cores to provide a mechanical structure for self-assembly of a supramolecular soluble system, in which the plurality of cores is an organic core that contains a core binding element for binding to a plurality of binding regions so as to form a first inclusion complex, where the core binding element contains a combinatorial carboxylated dipyridamole, and wherein the first inclusion complex is combinatorial carboxylated cobalamin with combinatorial carboxylated dipyridamole; and c) a plurality of terminators, with each terminator containing one binding terminator to form a bond with other binding sites of one of the plurality of binding components so as to form a second inclusion complex, where the primary terminal
  • the structural element has a plurality of binding regions of the binding components.
  • a binding element is a chemical moiety that binds to a specific binding region through one or more intermolecular bonds.
  • the linking element of the structural component and the linking region of the fastening element are specifically chosen so that they selectively bind to each other and the molecular recognition property can be used to identify the linking regions.
  • the binding region may contain combinatorial carboxylated cobalamin or carboxylated cobalamin or other derivatives of cobalamin.
  • the structural element is at least an inorganic or organic core.
  • Figure 1 shows a variant of the invention in the form of a structure of a soluble self-assembled nanoparticle containing in the form of a core a dynamic combinatorial derivative of cobalamide, a dynamic combinatorial derivative of dipyridamole as a structural component, a dynamic combinatorial derivative of basic oligopeptides and amino acids as binding components.
  • the core based on the self-assembling structure of a dynamic cobalamin derivative has an inorganic core selected from the group consisting of an inorganic nanoparticle, a metal nanoparticle, a gold nanoparticle, a nanoparticle silver silicon, a metal nanoparticle, a metal oxide nanoparticle, and any combinations of nanoparticles presented above.
  • inorganic nanoparticles include nanoparticles of a metal oxide or oxide of another element (eg, nanoparticles of silicon dioxide or nanoparticles of iron oxide), and nanoparticles of other inorganic compounds.
  • functional nanoparticles magnetic nanoparticles, quantum dots (for example, CdS, CdSe nanoparticles), or semi-solid conductive particles of metal oxides can be used.
  • the inorganic core may have a shape selected from the group including spherical, triangular, cubic, stellate, rod-shaped, shell-shaped, diamond-like, lamellar types, pyramidal, irregular, in the form of cell structures, and combinations thereof.
  • Inorganic nanoparticles are known in the art.
  • the inorganic core can bind to the binding regions of the nanoparticle components.
  • the binding component has a binding region that can contact the inorganic core directly.
  • the surface of the inorganic core was obtained using a variety of binding elements in such a way as to be able to communicate with multiple binding regions of the binder using one or more intermolecular forces.
  • a plurality of inorganic core particles may be present in the supramolecular structure.
  • a plurality of inorganic core particles may be associated with a plurality of binding components in such a way as to form a cross-linked network or hydrogel.
  • the continuous growth of the crosslinked network can be limited or terminated at will by termination components, which can also be associated with binding regions in the tie components.
  • the structural component is an organic core.
  • Organic cores may include derivatives of combinatorial self-assembling cobalamins, dendrimers, polymers, proteins, oligosaccharides, micelles, liposomes, vesicles, and combinations thereof.
  • the organic core may be a dendrimer, a polymer, or a polypeptide.
  • the structural component may include a dendrimer-based structural core, A polyamidoamine dendrimer (PAD), branched polyethyleneimine (RPE), linear polyethyleneimine, polylysine, polylactide, polylactide-co-glycoside, polyanhydride, poly-e-caprolactone, A polymethylmethacrylate, poly(N -isopropyl acrylamide), polypeptide, and combinations thereof.
  • the organic core is a polyamidoamine dendrimer or poly-L-lysine polymer.
  • the binding portions of the binding components interact with other elements that may be present as part of the organic structure of the core.
  • the organic core derivatized with multiple coupling elements such as, for example, combinatorial self-assembling dipyridamole derivatives.
  • the binders may bind to the binding regions of the binding component by one or more intermolecular forces, followed by self-assembly into a cross-linked network or hydrogel. The continuous propagation of the crosslinked network may be limited or terminated by terminators, which may also react with the bonding regions of the bonding component.
  • the binding region of the binding element can be selected depending on the type of binding, including based on the principle of molecular recognition.
  • FIG. 2 shows an embodiment of the invention in the form of self-organizing combinatorial dynamic derivatives of dipyridamole and the principle of their synthesis.
  • Numerous dendrimers are known in the art. The advantage of core dendrimers lies in their rapid synthesis and easy ability to functionalize due to the easy binding of elements.
  • the dendrimer can be synthesized by incorporating the required elements as part of the structure.
  • a reactive functional moiety may be present at each point of the terminal element added to the connecting element within the core.
  • specific dendrimers suitable for the invention include such as the polyamidoamine (PAM) dendrimer.
  • polymers are known in the art.
  • the advantage of using polymeric cores lies in its rapid synthesis and its ability to be easily functionalized fastener.
  • the structure of the polymer during synthesis may be included in the bonding element.
  • the reactive functional groups on the polymer may be derivatized with chemical moieties that provide the function of the bonding element.
  • polypeptides containing lysine residues in the structure with a reactive amino group (-NH2) can be functionalized with linking elements.
  • a polypeptide - poly-T-lysine two or more different structural components are present, in which case each structural component may have linking regions (groups) to form a bond with the linking component.
  • the structural component may be a polyamidoamine dendrimer derivatized with a linker/elements such as the KKRKRKRKR oligopeptide and linked to a combinatorial self-assembling carboxylated derivative of the same peptide.
  • K is one letter of the amino acid name lysine.
  • R - represents one letter of the amino acid name arginine.
  • the structural element may also be adamantine-derivatized inorganic nanoparticles, such as adamantine-derivatized metal nanoparticles, or adamantine-derivatized metal oxide nanoparticles, more specifically, for example, adamantine-derivatized gold nanoparticles.
  • terminating components occupy interfaces between linking components to limit continued propagation and growth of the network when terminating components are present in sufficient quantity relative to interaction regions in binding components.
  • the binder component and the structural component can self-assemble into a supramolecular structure, while the termination components can only occupy interaction areas and prevent further self-assembly (network growth) between the binding component and the structural component.
  • the degree to which the termination component limits the self-assembly process is based on the relative amount (concentration) of the binding components relative to the number of interaction sites on the binding components.
  • the concentration of terminating components reaches a sufficient level, self-assembly of three components is observed: (1) a structural component, (2) a binder component, and (3) terminating component, which leads to the formation of particles (nanoparticles) rather than a cross-linked network or hydrogel.
  • the advantage of this approach to the supramolecular production of nanosized particles is that the size of the final particles (nanoparticles) can be easily calculated by changing the relative concentrations of the components in the drug mixture.
  • the terminating component has a single bonding element that communicates with one of the interaction regions on the bonding component.
  • each terminating component has only one connecting element.
  • the binding element is a chemical moiety that is associated with the area of interaction of the binding component using one or more intermolecular forces. These terminating components interact with only one area of interaction on the connecting component. In this case, crosslinking between the termination component and the bonding component can be avoided.
  • the termination component may be a polymer, polypeptide, oligosaccharide, or small molecule and function as long as the termination component interacts with the binding sites of the binder component.
  • the termination component is a polymer that is obtained using a binder.
  • the terminating component is a polyethylene glycol derivatized with a binder, for example, contains maleic acid residues.
  • a supramolecular structure may have two or more termination components.
  • the supramolecular structure may have 2, 3, 4, 5, or 6 different termination components.
  • Each terminating component may have the same binding element, or they may have different connecting elements, but each connecting element will interact with the binding region of the connecting component.
  • Binding components have multiple binding sites that interact and bind to the structural component and the terminator component and may include a terminator component selected from the group consisting of unmodified cobalamin, dipyridamole, basic amino acids, an unmodified peptide such as KKRKRKRKR, and any combination thereof.
  • the binding region is a chemical moiety that binds to a structural component and a terminating component of one or more intermolecular forces.
  • two or more different binding components may be used, provided that both have selective interaction regions that bind to the structural and terminating components.
  • the binder may be a polymer, an oligosaccharide, or a polypeptide. Any suitable material with multiple bonding regions can be used as the binder. Polyethyleneimine or branched polyethyleneimine derivatized with multiple binding sites can also be used as a binder.
  • a specific example of a binder is a beta-cyclodextrin-derivatized branched polyethyleneimine.
  • Another example of a binder is poly-L-lysine derivatized with 0-cycle dextrin.
  • the binding regions and/or binding elements are molecular recognition elements.
  • the binding region forms a molecular recognition pair with a structural component or termination component.
  • FIG. 3 shows the principle of molecular recognition between different substances based on nucleotides as a structure, which has important applications in some embodiments of this invention.
  • Molecular recognition refers to a specific interaction between two or more molecules through one or more intermolecular forces.
  • Molecules involved in molecular recognition have molecular complementarity and are called paired molecular recognition or host-guest complex.
  • the terms "host” and “guests” do not attach special significance, but describe only two compounds that exhibit molecular complementarity, i.e. communicate with each other using molecular recognition. And the "host” and “guest” communicate with each other, while the two “host” connections do not.
  • Molecular recognition is a specific interaction, meaning that each molecular recognition element will bind to complementary molecules that have certain structural features.
  • the components of molecular recognition pairs bind to each other more tightly than in the case of non-specific binding, since the interactions that occur between the two molecular recognition elements are numerous.
  • molecular recognition pairs include small molecules - host/guest complexes (including, but not limited to inclusion complexes), pairs of complementary oligonucleotide sequences (for example, DNA-DNA, DNA-RNA or RNA-RNA that bind to each other another by hybridization), antibody-antigen, substrate protein, inhibitor protein, and protein-protein interactions (such as alpha-helical peptide chains and 0-L stranded peptide chains).
  • small molecules - host/guest complexes including, but not limited to inclusion complexes
  • pairs of complementary oligonucleotide sequences for example, DNA-DNA, DNA-RNA or RNA-RNA that bind to each other another by hybridization
  • antibody-antigen for example, substrate protein, inhibitor protein, and protein-protein interactions (such as alpha-helical peptide chains and 0-L stranded peptide chains).
  • the supramolecular structures are self-assembled by molecular recognition.
  • the binding regions on the binding component form a molecular recognition pair with binding elements on the building block.
  • Binding of elements on the terminal component also occurs with binding sites on the binding component to form a molecular recognition pair.
  • the molecular recognition pairs formed between the binding component and the structural component and may be the same as the molecular recognition pairs formed between the binding component and the terminal component, or they may be different.
  • the connecting element on the structural component may be the same as the connecting element on the terminating component, or they may be different, but both connecting elements are associated with the same connection area on the binding component.
  • molecular recognition pairs include molecular recognition pairs, combinations of molecular recognition pairs, and a plurality of multiple molecular recognition pairs.
  • Some exemplary embodiments of the invention include the use of molecular recognition pairs consisting of adamantane-0-cyclodextrin complex, diazobenzene-a-cyclodextrin complex, steroid-based molecular recognition pairs, pyrene-based molecular recognition pairs, steroids, rhodamine complexed with cyclodextrin, doxorubicin in complex with cyclodextrin, biotin-streptavidin, complementary nucleotide base pair, complementary nucleotide pair, complementary oligonucleotide pair, and combinations thereof.
  • At least one of the structural components, the connecting component or the terminating component includes a functional element.
  • a functional element may be a chemical moiety that imparts an additional function or activity to a supramolecular structure that is not present while the functional element is present.
  • the functional element may be a light-emitting (ie, fluorescent or phosphorescent) compound, such as a combinatorial self-assembling derivative of riboflavin. Fluorescent and phosphorescent supramolecular structures can be used, for example, in imaging studies in vitro or in vivo. For example, luminescent riboflavin is exposed to UV light and can be used as a functional element.
  • the functional element may also be a compound containing a radioactive or magnetically active isotope.
  • positron-emitting isotopes such as 64 Cu can be used to measure the biodistribution of supramolecular structures.
  • Other useful suitable isotopes would be obvious to one skilled in the art.
  • the functional element may be a target element, which is delivered due to the supramolecular structure in specific cells.
  • delivery systems with functional elements inside can be represented by oligonucleotides, antibodies, and small molecules that bind to cell surface proteins.
  • any chemical moiety that specifically binds to one or more cell surface receptors can be incorporated into a supramolecular structure to be a functional entity.
  • Cell surface proteins can be, for example, proteins on a cancer cell or on bacteria or fungi.
  • Specific examples of functional elements that are cellular targeting moieties for the present invention may be RGD and EGF, folic acid, transferrin, and include antibodies targeting cell surface markers such as, for example, Herceptin for Her2 in breast cancer cells.
  • a cell-permeable functional element that acts through the function of increasing the permeability of cell membranes can be selected as a functional element.
  • Specific examples of ligands that increase cell membrane permeability include the TAT ligand.
  • Various other ligands that act through cell membrane permeability can also be used in some embodiments of the present invention.
  • the supramolecular structure may have two or more functional elements.
  • a supramolecular structure may have two targeted functional elements as a means to increase the selectivity of delivery to the desired cells, or as a means to increase the binding affinity with several functional elements directed at a surface targeted protein-cell interaction.
  • Cell means biological cell.
  • multiple functional entities include supramolecular structures having targeted functional elements and having functional elements to increase cell permeability, as a means to combine the synergistic effects of improved drug transport to the cell and increase the permeability of the cell membrane.
  • a supramolecular structure having (1) an imaging component, a functional element that is a light emitting or radioisotope functional element, and (2) a targeted functional element for imaging target cells.
  • the present embodiments of the invention include the use of combinations of functional elements, such as two targeted functional elements, incl. a functional element for increasing the permeability of cell membranes, or two targeted functional elements, incl. functional element of visualization, as well as the use of combinations of the above functional elements.
  • the supramolecular structure includes two or more termination components, each of which may further include a functional element.
  • multiple functional elements can be introduced into the particle with multiple termination components.
  • a supramolecular structure may have (1) a terminator having no functional element and (2) a terminator having a target element. Termination components lacking a functional element can be exchanged with termination components having a functional element by treating the supramolecular structure with a secondary termination component or by treating the supramolecular structure with a mixture of other termination components.
  • a supramolecular structure can be obtained using a mixture of termination components, each of which will be included in the supramolecular structure.
  • the supramolecular structure may include a load.
  • the load is defined as chemical a fragment that can be encapsulated within the supramolecular structure and that can be released from the supramolecular structure.
  • the cargo may be associated with one or more structural components, a binding component, or a termination component.
  • the cargo is a chemical group that can non-specifically bind to the binding regions of the binder and which prevent the cargo from interfering with the self-assembly of the nanoparticles.
  • the cargo is a small molecule selected from the group consisting of drugs such as doxorubicin, taxol, rapamycin, cisplatin, other anticancer drugs useful in cancer chemotherapy, incl. protein, peptide, oligonucleotide, miRNA, plasmid, gene delivery molecules (systems), and any combination thereof.
  • drugs such as doxorubicin, taxol, rapamycin, cisplatin, other anticancer drugs useful in cancer chemotherapy, incl. protein, peptide, oligonucleotide, miRNA, plasmid, gene delivery molecules (systems), and any combination thereof.
  • supramolecular structures can deliver therapeutic proteins and oligonucleotides to a target cell, and these supramolecular structures themselves are used to protect therapeutic compounds, proteins and/or oligonucleotides from degradation.
  • the supramolecular structure may include two or more weights. The choice of the ratio and amount of two or more therapeutic compounds in the supramolecular structure ensures the correct delivery of drugs into the cell.
  • a plasmid can also be included in the supramolecular structure as a cargo. In many embodiments of the present invention, it is envisaged to encapsulate in supramolecular structures a variety of types of cargoes and various combinations of cargoes.
  • the present invention includes methods for obtaining the above-described free-molecular structures, by preparing a suspension of structural components and binders; adding binding components to said suspension.
  • the ratio of structural components for the binder components and terminating components are selected in accordance with a predetermined size of these supramolecular structures.
  • Structural, binding and terminating components self-assemble into supramolecular structures having a substantially predetermined size.
  • the predetermined size is at least more than 10 nm and less than 800 nm (nanometers).
  • Some embodiments of the present invention include methods for obtaining supramolecular structures.
  • One general example of a method for obtaining a supramolecular structure includes the following steps:
  • embodiments include a general method for obtaining a supramolecular structure include the following steps:
  • embodiments include a general method for obtaining a supramolecular structure, a step in which:
  • embodiments of the invention include a general method for obtaining a supramolecular structure, wherein:
  • embodiments of the invention include a general method for obtaining a supramolecular structure further comprising: - there is a choice of the ratio of the number of binding components to the number of terminating components.
  • the ratio of structural components for linking the components with the terminal components are selected in accordance with a predetermined size of the specified supramolecular structure.
  • Structural, binding and terminating components self-assemble (self-organize) into supramolecular structures, acquiring, in essence, a predetermined size.
  • a predetermined size is in the range from about 5 nm to 2000 nm.
  • a predetermined particle size in the range of at least 20 nm to 400 nm is desirable.
  • the size of the supramolecular structures can be easily controlled by changing the ratio between the components used to obtain the supramolecular structures. A wide variety of supramolecular structures of various sizes can also be easily obtained, the possibility of combinatorial synthesis also allows you to obtain different sizes of supramolecular structures, and optimize a specific function to ensure their activity.
  • the supramolecular structure can be easily obtained by combining the components together. At least three components self-assemble into a supramolecular structure. Additional components (structural, binding or terminating) or cargo connections (cargo or load) may also be used, provided that a minimum of elements are present. Additional components may include one or more functional elements.
  • the components can be replaced with other components bearing the appropriate binding elements or binding regions by treating the supramolecular structure with additional components.
  • one terminator components can be exchanged by processing the supramolecular structure for other terminator components (for example, enriched with functional elements).
  • structural or binding components can be exchanged by treating the supramolecular structure with additional structural or binding components. Suspension or a solution of the components may be sonicated to promote or assist in the component exchange reactions.
  • the size of the supramolecular structures can be easily controlled by changing the ratio between the components used to obtain the supramolecular structures.
  • a wide variety of supramolecular structures of various sizes can be easily obtained. It also enables combinatorial synthesis, as arrays of supramolecular structures can be generated based on their specific function and optimization of their activity.
  • the dimensions of the supramolecular structures can be adjusted after the supramolecular structures have been formed by treating prefabricated supramolecular structures with an additional component. For example, if a preformed supramolecular structure is treated with additional binder, the size of the structure will decrease. If the preformed supramolecular structure is treated with an additional structural component, the size will increase. Examples of such an effect are shown in the examples below.
  • the supramolecular structure can be dissociated naturally in vitro and in vivo, in accordance with some embodiments of the present invention.
  • Functional elements can also be easily adjusted using this method.
  • a component carrying a functional element can be included in the mixture used to obtain a supramolecular structure.
  • the proportion in which the functional elements are present in the supramolecular structure can be easily adjusted by changing the ratio between the functional elements. For example, if a functional element is present on a binder, the ratio of the binder having the functional element to the binder lacking the functional element determines the extent to which the functional element is present in the formed supramolecular structure. The same true when the functional element is present on the terminating component or the structural component.
  • the pre-assembled supramolecular structures can be treated with terminating components having functional elements. Part of the terminating components will exchange functional elements with the subsequent formation of a supramolecular structure. Many terminators with many different functional elements can be added to the supramolecular structure in a similar way. The extent to which a functional element is present on the resulting supramolecular structure is determined by the concentration of the terminating component for processing the preformed supramolecular structure.
  • the individual components can be easily obtained using well-known chemical synthesis methods.
  • the binders are selected depending on the type of intermolecular forces chosen to bind the components to each other. Based on the chemistry of molecular recognition, chemical moieties can be selected as the binding element or by the nature of the binding region.
  • inorganic cores can be synthesized using methods known in the art to provide the required elements on the surface when needed.
  • Organic compounds such as polymers and dendrimers can be synthesized using known methods with suitable binders.
  • organic cores, including polymers, dendrimers, and/or polypeptides, and having reactive functional groups modified with suitable linking elements or linking regions can also be prepared.
  • binders There are many methods for derivatizing organic compounds with suitable binders.
  • reactive functional groups of organic compounds such as hydroxyls, thiols, amines, carboxylic acids, halides, alkenes, alkynes, azides, and others can react or be activated to interact with a variety of other functional groups to form covalent bonds.
  • amine-containing compounds having a free -NH2 group can be reacted with amino-reactive group bearing entities such as isocyanates, isothiocyanates, and activated esters such as N-hydroxysuccinimide (NHS) esters.
  • binding elements can be easily added to any component.
  • the number of binding elements on a particular component may vary depending on the number of reactive sites and the number of reactive binding element used to obtain the component. For specific examples, see the examples below.
  • a linker may be required.
  • Various bifunctional crosslinkers for covalent binding to proteins are known to those skilled in the art, any of which may be used.
  • heterodifunctional crosslinkers such as succinimidyl-4-[N-maleimidomethyl]cyclohexane-1-carboxylate (SMCC) and melaimidobutyryloxysuccinimide ester (GMBS) can be used to react with amines (via succinimide bond esters) and then with the formation of a covalent bond with a free thiol (via maleimide).
  • crosslinkers such as succinim dil-3-(2-pyridyldithio)propionate (SPDP) can react with amines (via the succinimide ester) and form a covalent bond with the free thiol via thiol exchange.
  • Other bifunctional crosslinkers include suberic acid bis (N-hydrosuccinimide ester) which can react with two amines.
  • difunctional and heterobifunctional crosslinkers suitable for use with various surface modifications will be apparent to those skilled in the art.
  • 4-allyloxy-4-oxobutanoic acid has an alkene group at one end that can be used to link a thiol-ene to a thiol, and the other end has a carboxyl group that can be linked to an amine.
  • Other cleavable crosslinkers will be apparent to the skilled artisan. These include, for example, disulfide bonds, which are cleaved upon reduction.
  • Supramolecular structures have many applications, especially in the biological field.
  • the simple techniques required to obtain supramolecular structures allow the rapid preparation of supramolecular structures of various sizes or bearing specific functional elements.
  • the use of different materials for structural, binding and terminating components allows the use of a variety of utilities.
  • Supramolecular structures can be dissociated in in vitro and in vivo media according to some embodiments of the present invention. This makes it possible to release the cargo (payload) from the supramolecular structure.
  • Supramolecular structures can be used for gene therapy (in vivo) or for cell transfection (in vitro) by delivering genes or plasmids into cells.
  • the invention includes methods for delivering a gene into a cell by contacting the cell with the supramolecular structure described herein carrying a plasmid as cargo.
  • Treatment of a cell with a supramolecular structure results in the internalization of the supramolecular structure, followed by the release of the plasmid into the cell. This can lead to efficient "transfection" of the target cell with the plasmid of interest.
  • any plasmid carrying any gene can be introduced into a cell in this way.
  • targeting elements (target elements) and/or penetration (penetration) into cells can improve the specificity and/or internalization of cells.
  • the invention also includes methods for delivering therapeutic compounds by treating a cell with the supramolecular structure described herein with the therapeutic compound as cargo.
  • the therapeutic compound may be, for example, a protein or peptide (including antibodies), an oligonucleotide (eg, siRNA), or a small molecule.
  • the small molecule can be, for example, an anticancer (eg doxorubicin, taxol, paclitaxel, cisplatin or rapamycin), antibiotic, antibacterial or antifungal agent.
  • Functional elements of the supramolecular structure can improve the targeting, internalization or distribution of cells. More than one therapeutic compound can be delivered in a single supramolecular structure, and if necessary, the ratio of therapeutic compounds can be controlled.
  • supramolecular structures described herein include photothermotherapy techniques by treating cells with the supramolecular structures described herein containing gold nanoparticles as structural components.
  • compositions eg, pharmaceutical compositions
  • a pharmaceutical composition of the invention will contain an effective amount (eg, a pharmaceutically effective amount) of a composition of the invention.
  • composition of the invention may be formulated as a pharmaceutical composition which contains the composition of the invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e. the material can be administered to a subject without causing any undesirable biological effects or which does not interact in an adverse manner with any of the other components of the pharmaceutical product or composition in which it is contained.
  • the carrier will naturally be chosen to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as is well known to those skilled in the art.
  • pharmaceutically acceptable carriers and other components of pharmaceutical compositions see Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, 1990.
  • suitable pharmaceutical carriers include, for example, water (including sterile and/or deionized ), suitable buffers (such as PBS), saline, cell culture medium (such as DMEM), artificial cerebrospinal fluid, and the like.
  • compositions or kit of the invention may contain other pharmaceutical preparations in addition to the compositions of the invention.
  • the other agent(s) may be administered at any appropriate time during treatment of the patient, either simultaneously or sequentially.
  • One skilled in the art will appreciate that the particular formulation will depend in part on the particular agent used and the route of administration chosen. Accordingly, there is a wide variety of suitable compositions of the compositions of the present invention.
  • Formulations suitable for topical administration directly to the CNS include, for example, suitable liquid carriers or creams, emulsions, suspensions, solutions, gels, creams, pastes, foams, lubricants or sprays. Local injection into the CNS is possible when opening the CNS with a wound or during surgery.
  • suitable formulation may be selected, adapted, or developed based on a particular application. Dosages for the compositions of the present invention may be in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unit doses for animals (eg, humans), each unit containing a predetermined amount of an agent of the invention, alone or in combination with other therapeutic agents calculated in an amount sufficient to obtain the desired effect in combination with a pharmaceutically acceptable diluent, carrier or excipient.
  • the person skilled in the art can readily determine the appropriate dose, schedule, and route of administration for the precise formulation of the composition used to achieve the desired effective amount or effective concentration of the agent in an individual patient.
  • the dose of the composition of the invention administered to an animal, in particular a human, in the context of the present invention should be sufficient to affect at least the detectable magnitude of the diagnostic or therapeutic response in the individual within a reasonable period of time.
  • the dose used to achieve the desired effect will be determined by a variety of factors, including the efficacy of the particular agent administered, the pharmacodynamics associated with the agent in the host, the severity of the disease state of infected individuals, the presence of other drugs administered to the subject, and so on.
  • the size of the dose will also be determined by the presence of any adverse side effects that may accompany the particular agent or composition used. It is generally desirable to minimize side effects as much as possible.
  • the dose of biologically active material will vary; suitable amounts for each particular agent will be apparent to the skilled artisan.
  • kits applicable to any of the methods disclosed herein, either in vitro or in vivo.
  • a kit may include one or more compositions according to the invention.
  • the kits contain instructions for performing the method.
  • Optional elements of the kit include suitable buffers, pharmaceutically acceptable carriers and the like, containers or packaging materials.
  • Kit reagents may be in containers in which the reagents are stable, such as in lyophilized form or in stabilized liquids.
  • the reagents may also be in single use form, for example in single dose form.
  • the CDC composition may be administered orally, or may be administered intravascularly, subcutaneously, intraperitoneally by injection, aerosol, bladder, topically, and so on.
  • inhalation methods are well known in the art.
  • the dosage of the therapeutic composition will vary widely depending on the particular antiviral CDC administered, the nature of the disease, frequency of administration, route of administration, clearance of the agent used from the host, and the like. The initial dose may be higher with subsequent lower maintenance doses.
  • the dose can be administered at a frequency of once a week or once every two weeks, or can be divided into smaller doses and administered once or more times a day, twice a week, and so on to maintain an effective dose level.
  • oral administration requires a higher dose than intravenous administration.
  • the compounds of the present invention can be included in various compositions for therapeutic administration. More specifically, the compounds of the present invention may be included in pharmaceutical compositions in combination with suitable pharmaceutically acceptable carriers or diluents and may be incorporated into preparations in solid, semi-solid, liquid or gaseous forms such as capsules, powders, granules, ointments, creams, foams, solutions, suppositories, injections, inhalants, gels, microspheres, lotions and aerosols. As such, administration of the compounds may be by various routes, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal, and so on.
  • the antiviral CCMs of the invention may be distributed systemically after administration, or may be localized using an implant or other composition that retains the active dose at the site of implantation.
  • the compounds of the present invention can be administered alone, in combination with each other, or they can be used in combination with other known compounds (eg, perforin, anti-inflammatory agents, etc.).
  • the compounds may be administered in the form of their pharmaceutically acceptable salts.
  • the following methods and auxiliaries are given by way of example only and do not limit the invention in any way.
  • all compounds can be used alone or in combination with suitable additives for the production of tablets, powders, granules or capsules, for example with conventional additives such as lactose, mannitol, corn starch or potato starch; with binding agents such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; with talc or magnesium stearate and, if necessary, with diluents, buffering agents, wetting agents, preservatives and flavorings.
  • suitable additives for the production of tablets, powders, granules or capsules, for example with conventional additives such as lactose, mannitol, corn starch or potato starch; with binding agents such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants such as corn starch, potato starch or sodium carboxymethyl cellulose; with talc or magnesium stearate and
  • the compounds may be incorporated into injectable compositions by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol; and, if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives. Connections can be used in an aerosol composition for inhalation administration, including using nebulizers.
  • the compounds of the present invention may be incorporated into suitable pressurized propellants such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • the compounds can be incorporated into suppositories by mixing with various bases such as emulsifying bases or water soluble bases.
  • the compounds of the present invention can be administered rectally using suppositories.
  • the suppository may contain excipients such as cocoa butter, carbovax and polyethylene glycols, which melt at body temperature but remain solid at room temperature.
  • Unit dosage forms for oral or rectal administration such as syrups, elixirs and suspensions, where each unit dose, for example, a teaspoon, tablespoon, tablet or suppository, may contain a predetermined amount of a composition containing one or more compounds of the present invention.
  • unit dosage forms for injection or intravenous administration may contain a compound of the present invention in a composition in the form of a solution in sterile water, saline, or other pharmaceutically acceptable carrier.
  • Implants for sustained release compositions are well known in the art. Implants are made in the form of microspheres, plates, etc. from biodegradable or non-biodegradable polymers. For example, polymers of lactic and/or glycolic acid form a degradable polymer that is well tolerated by the host.
  • the implant containing the antiviral combinatorial cobalamides according to the invention is located close to the site of infection (in the case of a respiratory viral infection, the lungs and bronchi), so that the local concentration of the active agent is increased compared to other areas of the body.
  • unit dosage form refers to physically discrete units suitable for use as single doses in humans and animals, each unit containing a predetermined amount of the compounds of the present invention, which, according to calculations, is sufficient to provide the desired effect together with a pharmaceutically acceptable diluent , carrier or excipient. Description The unit dosage forms of the present invention depend on the particular compound used and the effect to be achieved, as well as the pharmacodynamics of the compound used in the host organism. Pharmaceutically acceptable excipients are usually available, such as excipients, adjuvants, carriers or diluents.
  • Typical doses for systemic administration are in the range of 0.1 pg (picograms) to 1000 milligrams per kg of subject's body weight per administration.
  • a typical dosage may be one tablet to be taken two to six times a day or one sustained release capsule or tablet to be taken once a day with a proportionately higher content of the active ingredient.
  • the sustained release effect may be due to capsule materials dissolving at different pH values, slow release capsules under osmotic pressure, or any other known controlled release method.
  • dosage levels may vary depending on the particular compound, the severity of the symptoms, and the subject's susceptibility to side effects. Some of the specific compounds are more effective than others.
  • Preferred doses of this compound can be readily determined by those skilled in the art in a variety of ways.
  • the preferred method is to measure the physiological activity of the compound.
  • One method of interest is the use of liposomes as a delivery vehicle.
  • the liposomes fuse with the cells of the target area and deliver the contents of the liposomes to the cells.
  • Contact of liposomes with cells is maintained for a time sufficient for confluence using various methods of maintaining contact, such as isolation, binding agents, and the like.
  • the liposomes are intended to be aerosolized for pulmonary administration.
  • Liposomes can be made from purified proteins or peptides that mediate membrane fusion, such as Sendai virus or influenza virus.
  • the lipids may be any useful combination of known liposome-forming lipids, including cationic or zwitterionic lipids such as phosphatidylcholine.
  • the remaining lipids are usually neutral or acidic lipids such as cholesterol, phosphatidylserine, phosphatidylglycerol, and the like.
  • To obtain liposomes the method described by Kato et al. (1991) J. Biol. Chem 266: 3361.
  • lipids and a composition for incorporation into liposomes containing combinatorial supramolecular cobalamides are mixed in a suitable aqueous medium, suitably a saline medium, where the total solids content will be in the range of about 110 wt%.
  • a suitable aqueous medium suitably a saline medium
  • the tube is placed in a warm water bath at approximately 25-40°C and this cycle is repeated approximately 5-10 times.
  • the composition is then sonicated for a suitable period of time, typically about 1-10 seconds, and optionally further mixed with a vortex mixer.
  • the volume is then increased by adding an aqueous medium, typically increasing the volume by about 1-2 times, followed by stirring and cooling.
  • the method makes it possible to include supramolecular structures with a high total molecular weight in liposomes.
  • compositions with other active agents are provided.
  • antiviral supramolecular structures have been considered for use in the present methods.
  • One antiviral supramolecular structure is called KS.
  • the antiviral KS of the invention may be formulated with other pharmaceutically active agents, in particular other antiviral, antimicrobial or anticancer agents.
  • Other agents of interest include a wide range of antiviral mononucleotide derivatives and other RNA polymerase inhibitors known in the art.
  • Classes of antiviral agents include interferons, lamivudine, ribavirin, and so on; amantadine; rimantadine such as zinamivir, oseltamivir and so on; acyclovir, valaciclovir, valganciclovir, etc.
  • antivirals include adefovir, vbacavir, didanosine, emtricitabine, lamivudine, nelfinavir, ritonavir, sakinavir, daclatasvir, stavudine, tenofovir, efavirenz, nevirapine, indinavir, lobalavir and ritonavir and ritonavir. cholecalciferol. Cytokines such as interferon gamma, tumor necrosis factor alpha, interleukin 12, and so on, can also be included in the composition along with the KS of the present invention. The present invention is further described by the following examples, which should not be construed as limiting the scope of the invention.
  • Alkylation is defined as the introduction of an alkyl substituent into an organic molecule.
  • Typical alkylating agents are alkyl halides, alkenes, epoxy compounds, alcohols, less often aldehydes, ketones, esters, sulfides, diazoalkanes.
  • Alkylation catalysts are mineral acids, Lewis acids, and zeolites. Alkylation is widely used in the chemical and petrochemical industries.
  • Ensemble or supramolecular ensemble is a term from supramolecular chemistry.
  • the objects of supramolecular chemistry are ensembles spontaneously constructed from complementary geometrically and chemically corresponding molecular fragments.
  • more than 100 different derivatized supramolecular structures can be synthesized due to possible chemical permutations and combinations. It is noteworthy that intermolecular ionic and hydrogen bonds are necessarily formed between their molecules, and derivatized supramolecular structures have a significantly higher biological activity than the original cyanocobalamin molecule.
  • a drug was made that is effective in vivo against influenza, herpes, in Ovo models (in eggs), and bovine coronavirus.
  • a combinatorial mixture of carboxymethylcobalamin was used in the form of a supramolecular ensemble without separation into individual components.
  • a combinatorial library is a set of a large number of chemical compounds, proteins, genes, or oligonucleotides that allows you to quickly search for target genes or target proteins.
  • a set of combinatorial libraries may consist of millions of different chemicals, or, for example, a set of recombinant DNA molecules obtained by inserting various antibodies into the cDNA light and heavy chains.
  • Combinatorial synthesis involves the synthesis by combinatorial chemistry of many simultaneous reactions between three or more reactants to form combinatorial synthesis products that include hundreds of derivatives of the combined reactants. Derivatives of the combined reagents can be separated chromatographically to confirm their structure and study biological activity. Recent approaches include the use of unseparated and/or crude mixtures of combinatorial synthesis products for various reasons, including the fact that such mixtures of combinatorial synthesis products have larger and more variable biological activity profiles than the biological profiles of the individual components of the combinatorial synthesis products. synthesis.
  • a therapeutically effective amount is a term for the present invention that refers to the amount of a drug.
  • a therapeutically effective amount of combinatorial derivatives of cyanocobalamin is an amount that provides a therapeutically effective antiviral activity.
  • ECPs are expected to be different for different viruses and different animal models.
  • EXAMPLE 1 is an example of the application of the present invention in practice using combinatorially modified cobalamin, which serves as the core of the supramolecular structure.
  • This core is synthesized using combinatorial derivatives of cyanocobalamin with antiviral properties and is called KS.
  • the created pharmaceutical compositions and dosage forms differ in that the alkylated derivatives of cyanocobalamin are an undivided combinatorial mixture of derivatives from a monosubstituted to a fully substituted derivative for all groups R1-R7 of the following structure shown in FIG. 5, where at least one of the substituents R1-R7 is -CH2-COOM at any position and M is a metal or hydrogen atom.
  • M can also be represented by one from metals: K, Mg, Ca, Cu, Fe, Li, Na, Ba, Ag, Pt, Au, Ti or Sb.
  • the pharmaceutical composition may additionally contain vanillin in the composition of the dosage form and cholecalciferol.
  • the pharmaceutical composition may further comprise unsubstituted methylcobalamin, dihydroxycobalamin (hydroxycobalamin), cobamamide, or a mixture thereof in dosage form.
  • compositions provided may, for example, be formulated into a variety of dosage forms, including, but not limited to, an aerosol formulation for use in a nebulizer or spray, for injectable formulation use for intramuscular injection (IM), intravenous (IV) injection, and intravenous ( I VI) infusions.
  • IM intramuscular injection
  • IV intravenous
  • I VI intravenous infusions.
  • a virucide is defined as any physical or chemical agent that inactivates or destroys viruses. This is different from an antiviral drug, which inhibits the proliferation of the virus inside the cell (Virucide, Wikipedia, 2020). The difference between virucidal and virucidal is shown to be that the virucidal action is part of the virucidal action, while the virucidal action means the complete destruction of viruses, (viricidal or virucidal action, Wikki-diff, 2020).
  • EXAMPLE 2 is an example of the synthesis of a combinatorial mixture of carboxymethylated cyanocobalamin, which can be used to create an antiviral supramolecular structure called COP.
  • FIG. 6 shows the HPLC (high pressure liquid chromatography) chromatogram of the starting cyanocobalamin.
  • the original cobalamin gives one absorption line when using a UV detector.
  • FIG. 7 shows an HPLC chromatogram of a combinatorial cyanocobalamin derivative. The chromatogram shows that the peak of the derivative is located elsewhere. Derivatives with a more hydrophilic region leave the HPLC column earlier and thus the derivative chromatogram feature is expanded and split into additional bands. This suggests that cyanocobalamin derivatives may have intramolecular and supramolecular ionic and hydrogen bonds that remain unchanged during the HPLC separation process performed under classical conditions using gradient HPLC.
  • TLC thin layer chromatography
  • CGEP capillary gel electrophoresis
  • Other chemical combinations can be used to derivatize cyanocobalamin, including the use of carboxylic acid anhydrides and polycarboxylic acid anhydrides, carboxylic acid halides and halocarbons.
  • methylcobalamin, hydroxocobalamin (hydroxycobalamin), and/or cobamamide can be used as the primary cobalamin for derivatization.
  • the antiviral activity of the derivatives was studied by screening on models of the influenza virus H1N1 (Inf), the reference strain of the vesicular stomatitis virus (Vesic. -VVS) and herpes simplex virus type 1 (Negr. - strain L-2 ), coronavirus - avian infectious bronchitis virus (IBV) in mattresses on a culture of chicken fibroblasts according to the degree of degradation (cytopathic effect, detachment from the bottom of the mattress).
  • H1N1 influenza virus
  • Vesic. -VVS the reference strain of the vesicular stomatitis virus
  • herpes simplex virus type 1 Negr. - strain L-2
  • IBV coronavirus - avian infectious bronchitis virus
  • the degree of "desquamation" of cells was determined by staining the culture with a vital dye, the concentration of which was determined spectrophotometrically relative to a healthy monolayer and an empty well.
  • the results of the in vitro studies are shown in Table 1 below.
  • KS-based dosage forms have an antiviral effect that can protect 50% or more of the infected culture cells.
  • Dosage forms with vanillin and others derivatives of cobalamin statistically significantly (P ⁇ 0.05) exceed the effectiveness of the pure substance CS.
  • PT transplantable bovine embryonic kidney cells
  • Tr transplantable bovine tracheal cells
  • Hep-2 transplantable human laryngeal cancer cells
  • HeLa stands for transplantable human uterine cancer cells.
  • Influenza H1N1
  • vesicular stomatitis Indiana strain
  • coronavirus X 343/44
  • herpes simplex virus type 1 L-2 strain
  • avian infectious bronchitis coronavirus IEK-KL2 strain
  • CPE cytopathic effect
  • MTC maximum tolerated concentration
  • a dose of the drug in a volume of 0.2 ml was used on 10-11-day-old chicken embryos (5 embryos per breeding MP).
  • the dose of the drug was injected into the allantoic cavity of the chick embryo as follows. Embryos at the age of 10-11 days were subjected to ovoscopy and marked with an air-cushioned pencil on the side opposite the location of the embryo, where there are fewer blood vessels.
  • the place marked with a pencil was disinfected with an alcoholic solution of iodine, then the shell was pierced, and then 0.2 ml of the drug dose was injected into the hole using a tuberculin syringe into the allantois cavity using a syringe needle to a depth of 10 °. 15 mm parallel to the longitudinal axis of the egg.
  • the well was again disinfected with an alcoholic solution of iodine and sealed with paraffin wax.
  • the egg was then placed for incubation using a thermostat set at 35-37 ° C for 72 hours.
  • the eggs Before opening the eggs, they were placed for 18-20 hours in a refrigerator at a temperature of 24 ° C in order to narrow the blood vessels of the embryo as much as possible. After that, the eggs were placed on a tray with a blunt end up. Then the shell over the air cushion was disinfected with an alcohol solution of iodine and 96% ethanol. The egg was broken and the embryo was removed with sterile forceps. The membrane lining the bottom of the air sac was also removed after separating it from the underlying chorioallantoic membrane. The number of live and normally developing embryos after 24 and 48 hours of incubation in a thermostat at 37°C was counted to calculate LDso and MTD according to the Kerber method.
  • KS and its dosage forms are not toxic to cell cultures at a dose of KS greater than 50 mg/ml.
  • the drug solution was lyophilized and then diluted to a concentration of 5%.
  • the MTS for cell cultures treated with both pure CS and its dosage forms is more than 50 mg/ml, which indicates the low toxicity of the proposed agent.
  • KSO KSO
  • KSO which is a liquid antiviral formula (KS + van + CO).
  • Aqueous solutions of KSO in various doses were injected into the allantoic cavity of 15 chicken embryos in a volume of 0.2 ml 12 hours after the virus was injected at a working dose (100 TCD50 / 0.2 ml).
  • Each experiment was accompanied by a test virus control at a working dose. Infected and uninfected (control) embryos were incubated at 36°
  • the minimum effective concentration (IEC) in relation to the influenza virus, which inhibits the synthesis of the virus in 50% of the cells, is 0.005 mg/ml with increasing dilution.
  • the effectiveness of CSR decreases and is dose-dependent. This fact indicates that KSO has a direct antiviral effect on the H1N1 influenza virus.
  • the term 1g for the present invention means decimal logarithm or decimal logarithm as opposed to natural logarithm.
  • Antiviral activity against cytopathic viruses vesicular stomatitis virus, coronavirus and measles virus was determined in the culture of the above cells. The reaction was carried out as follows: 0.2 ml of the corresponding virus at a working dose (100 TCA50/0.2 ml) was added in a volume of 0.2 ml to a 2-day washed cell culture. Then 0.8 ml of maintenance medium was added. When CPE (cytopathic effect) appeared in the culture, KSO was administered in various doses. As a control, the same was done with test viruses without preparation. Cells were incubated at 37°C in an incubator. Experimental data and observations were carried out on days 3, 5 and 7 experiment. A decrease in the virus titer under the action of the study drug by 2 ⁇ g or more compared with the control was evaluated as a manifestation of antiviral activity.
  • the CTI of the drug is 1000.
  • KSO was active against all viruses studied.
  • the CSR drug is not associated with the specific characteristics of the virus or cell culture, but affects the mechanisms common to all cells.
  • the tests were carried out in 96-well plastic plates with strain D-52 of porcine transmissible gastroenteritis virus (TGS) with an initial titer of 10 4 TCD50 / ml (tissue cytopathic doses) in a transplanted piglet test cell culture (PTR) and a strain of large bovine diarrhea virus "Oregon" with an initial titer of 10 7 TCD50 / ml in a transplanted culture of saiga kidney (PS) cells.
  • TCS porcine transmissible gastroenteritis virus
  • PTR transplanted piglet test cell culture
  • PS saiga kidney
  • virucidal (inactivating) effect When determining the virucidal (inactivating) effect, different doses of the compound solution were mixed in equal volumes with the virus-containing material and incubated in a thermostat at 37°C for 24 hours. The virus-containing material was used as a control, to which placebo (saline) and cultures of intact cells were added instead of the compound solution. The mixtures after contact were titrated in parallel with the control. Results were determined 72-144 hours after incubation at 37°C, after the overt manifestation of CPE in virus controls. The viricidal effect was determined by the difference in virus titers in the experiment and control and expressed as 1g TCD50.
  • the KSO compound has a virusostatic (inhibiting) and virucidal (inactivating) effect on TGS viruses and diarrhea in cattle, and it can be used to create chemotherapeutic agents for the treatment and prevention of infectious diseases of viral etiology.
  • herpes infections are important to study because herpes diseases are widespread and extremely diverse in their clinical manifestations. Models of experimental herpes in animals are increasingly used in the study of new antiviral agents.
  • One of the clinical forms of systemic herpes namely herpetic encephalitis, is easily caused in guinea pigs, hamsters, rats, mice, rabbits, dogs and monkeys.
  • Herpetic keratoconjunctivitis in rabbits (average weight 3.5 kg) was induced by applying an infectious material (herpes simplex virus type 1 strain L-2) to the scarified cornea after the eye had been anesthetized with dicaine instillation and the cornea several times. Then the eyelid was closed and rubbed in a circular motion.
  • the dose of the virus was 0.05 ml, the dose was 6.75 1g TCD50/ml.
  • 16 rabbits were used. Ten rabbits were injected with KSO (daily from the second day of infection until day 14) at a dose of 20 mg/kg, six rabbits were injected with placebo 0.9% sodium chloride solution.
  • the experimental group of rabbits were injected with CSO into the ear vein at a dose of 20 mg/kg of body weight, 0.9% sodium chloride solution was injected into the ear vein of the control group. This procedure was repeated once daily for two weeks. All animals of the experimental group survived, the HSV1 antigen in the blood was not detected on the 13-14th day, and encephalic manifestations ended on the 7th day of the drug administration, and 2 animals of the control group died. On the 14th day, one animal of the experimental group died, while 6 animals died in the control group that did not receive KSO.
  • the KSO efficacy index was 83.3% in the rabbit model of herpetic keratoconjunctivitis/encephalitis, and the experimental group of rabbits gained weight.
  • the chemotherapeutic index was 1000.
  • KSO is an effective antiviral drug with a wide spectrum of action and low toxicity.
  • the effect of the KSO drug on the propagation of vaccine virus strains was measured based on the effect of KSO in reducing the titer of the respective specific antibodies.
  • Many antiviral drugs inhibit the reproduction of live vaccine strains of viruses, while inhibiting the synthesis of specific antiviral antibodies. This effect is associated with insufficient intensification of the infectious process by the vaccine and a weak immune response. For example, birds with infectious bursal disease exposed to a live vaccine may develop excessive antibodies, so the bird becomes hypersensitive to other viruses, loses weight, and increases mortality.
  • the use of the KSO drug was supposed to show the presence of antiviral properties in several areas: a decrease in excessive levels (titers) of antibodies, a decrease in morbidity (safety), an increase in weight gain.
  • broiler chickens were selected on days 36 and 41, 15 animals per group. KSO was taken the day before vaccination with live vaccines against IBD, Gumboro disease (HD) and coronavirus infectious bronchitis (IB). Control birds were broiler chickens that were not fed KSO but were vaccinated.
  • IBD Gumboro disease
  • IB coronavirus infectious bronchitis
  • KSO has a direct (not immunostimulatory) effect against all three viruses.
  • the greatest inhibitory effect was observed in the group with infectious bronchitis - a decrease in antibody titer by 2000 units.
  • antibody titers increased from 3000 units to 3600 units, indicating that the live vaccine virus is efficiently reproducing in the bird.
  • CSR allows you to increase the growth of broiler chickens by 5% and reduce mortality by 1%.
  • KSO has a direct antiviral effect, inhibiting the reproduction of infectious bursal disease, Gambaro disease and coronavirus infectious bronchitis viruses.
  • KSO provides moderate suppression of vaccine virus replication, providing sufficient levels of protective antibodies and preventing bird immunity depletion and a corresponding reduction in weight gain and increased mortality.
  • broiler chickens also called simply broilers
  • characteristic changes were observed for colibacillosis, coccidiosis, as well as numerous hemorrhages on the mucous membranes of the rectum, in the zone of transition of the glandular stomach into the muscular, basal glands.
  • the contents of the glandular stomach are colored green.
  • the death of broilers reached 15-20%.
  • NCV Newcastle disease virus
  • HADR hemagglutination delay test
  • Immunity was determined at 42 days of age in HADR. At the same time, the clinical condition of the bird, the percentage of conservation, growth and feed costs were taken into account.
  • the death of broilers was in the control - 9.8%, while the percentage of death decreased in the experimental groups: 2.9; 4.5 and 4.4 times, respectively, compared with the control.
  • the average daily weight gain in the experimental groups ranged from 50 to 55 grams, while in the control groups the average weight gain was 46 grams.
  • the optimal scheme for the use of KSO for broilers in regions with a difficult epizootic situation with BNR is the use of the drug at a dose of 0.03 ml/kg of live weight 3 days before vaccination and 7 days before vaccination. 10 days after vaccination against NBR.
  • the use of the drug according to the above scheme leads to a six-fold increase in the average titer of specific antibodies to the BNK virus and a four-fold decrease in the mortality of broiler chickens.
  • Example 3 concerns the preparation of a supramolecular combinatorial mixture of dipyridamole (CD) derivatives as a binding and terminating component.
  • FIG. 8 is a schematic of Example 3 for a combinatorial synthesis of dipyridamole (CD) derivatives.
  • carboxylic acid anhydride modifiers halides of carboxylic and polycarboxylic acids such as succinic, maleic, fumaric, lactic, propionic, other halogen derivatives such as chloromethane, bromoethane, chloropropane, cyclic alkylating compounds such as oxirane or propiolactone can optionally be used to obtain combinatorial derivatives of dipyridamole.
  • Amino groups as part of the residual morpholine and pyrimidine core can be protonated and protected from modification under the given reaction conditions.
  • modifiers such as succinic anhydride or acetic anhydride can be used and introduced simultaneously and sequentially, or, succinic anhydride can be first introduced and heated in the mixture using a reflux condenser, and then acetic anhydride can be introduced and reheat the mixture.
  • succinic anhydride instead of using succinic anhydride as a modifier, other embodiments of the present invention are contemplated using alternative synthetic approaches that use related chemical modifiers, including, for example, anhydrides such as maleic anhydride, aconitic anhydride , glutaric acid or phthalic acid, anhydride; acids such as, for example, acetic anhydride, ethyl formic acid or monochloroacetic acid; and various alkylating agents including, for example, propiolactone, ethylene oxide, methyl chloride, ethyl chloride, or propyl chloride.
  • C 13 NMR carbon-13-nuclear magnetic resonance
  • HPLC was performed on an HPLC column (Milichrom A-02 microcolumn chromatograph with a gradient of acetonitrile (5-100%)/0.1 M perchloric acid and 0.5 M lithium perchlorate).
  • CD on the HPLC chromatogram shows one distinct broad peak and is not separated into components, although the retention time differs both from the original dipyridamole and from its fully substituted derivatives.
  • the complex supramolecular structures formed between 12 different combinatorial CD derivatives were not separated chromatographically by this HPLC column method.
  • this combinatorial derivative of dipyridamole (CD) was not separated by thin layer chromatography (TLC) using acetonitrile:water as the mobile phase and UV detection was used.
  • CD-TCX showed only one band, which did not match any of the resulting derivatives.
  • Figure 9 shows the TLC of the combinatorial mixture (IV), which is less mobile than the original unmodified dipyridamole (I) and is the lightest band on TLC.
  • Fully acylated dipyridamole (lb) and succinylated dipyridamole (1c) bands appear on TLC between the TLC bands of natural dipyridamole and combinatorial dipyridamole.
  • the combinatorial band of dipyridamole was not resolved into its complex supramolecular structures by 2D TLC or by HPLC (data not shown).
  • Various supramolecular combinatorial derivatives of dipyridamole have been obtained in synthesis reactions using various molar ratios of modifiers.
  • a solid phase sandwich ELISA was used with cyclic AMP (enzymatic immunoassay). The reaction was stopped by adding a double volume of 1% TC A.
  • Table 9 above provides experimental data which, taken as a whole, reveal unexpected enzyme inhibition efficacy for some embodiments of the present invention. From Table 9, Item #3, it can be seen that the ED50 for inhibition of cAMP phosphodiesterase by supramolecular combinatorial derivatives of dipyridamole is the lowest (0.01 ⁇ g/mL ED50) when the molar ratio of the three reactant modifiers (m, kl and k2) is 44:61 :60. Note that with w equal to 44, a rather small decrease in the number of molar ratios kl and k2 from 70.70 to 60.61 causes an amazing 10,000-fold improvement in cAMP phosphodiesterase inhibition.
  • the following table 10 shows the compositions of the studied pharmaceutical compositions (FC, CD).
  • the animals received the same composition with the same substances (as Carbopol gel) but without CD (FC).
  • Example 3 concerns combinatorial basic amino acids and a basic oligopeptide as a linking component.
  • the combinatorial mixture of KKRKRKRKR oligopeptides is hereinafter referred to as KR.
  • Oligopeptide KKRKRKRKR is preliminarily obtained using a standard method for obtaining a peptide on a peptide synthesizer or by genetic engineering.
  • m number of moles of the original oligopeptide.
  • the molar ratio to obtain the maximum number of different derivatives (1532 different molecules) is 3:3:1 (succinic anhydride: phthalic anhydride: oligopeptide KKRKRKRKR).
  • FIG. 10 shows the result of HPLC analysis of the original KKRKRKRKR peptide.
  • the original peptide when using a detector in the region of 280 nm gives one absorption band.
  • Rice. 11 shows the result of HPLC analysis of the combinatorial peptide derivative KKRKRKRKR.
  • the peptide peak is not just located in a different place - in the area of a more hydrophilic region, but is broadened, divided for 3 additional lanes.
  • HPLC data suggest that among the 1532 different peptide derivatives, there are ionic and hydrogen intramolecular/supramolecular bonds that do not break during the separation process under classical gradient HPLC conditions. Thin layer chromatography and capillary gel electrophoresis also failed to separate supramolecular derivatives into separate fragments.
  • modifiers are carboxylic and polycarboxylic acid anhydrides, carboxylic acid halides, and/or halocarbons.
  • Peptides can be obtained by standard methods, including the use of peptide synthesizers, genetic engineering methods and/or recombinant technology methods known in the art.
  • the antiviral activity of the derivatives was studied by screening on models of influenza virus H1N1 (Inf), a reference strain of vesicular stomatitis virus (Vesic.-VVS) and herpes virus type 1 (Negr . - strain L-2) in the table on the culture of chicken fibroblasts, depending on the degree of degradation (cytopathic effect, exfoliation from the bottom of the hole).
  • the degree of "degradation” of cells was determined by staining the culture with a vital dye, the concentration of which was determined spectrophotometrically in relation to a healthy monolayer and an empty well.
  • the results of the in vitro studies are shown in Table 11 below.
  • KR2 KKRKSTRKR oligopeptide
  • the molar ratio to obtain the maximum number of different derivatives is 3:3:1 (succinic anhydride: phthalic anhydride: oligopeptide KKRKSTRKR).
  • FIG. 12 shows the result of HPLC analysis of the original KKRKSTRKR peptide.
  • the original .peptide when using a detector in the region of 280 nm, gives one absorption band.
  • Rice. 13 shows the result of HPLC analysis of the combinatorial peptide derivative KKRKSTRKR. As can be seen from the chromatogram, the peptide peak is not just located in a different place, but in a more hydrophilic region, and it is rather broad, divided into 4 additional bands.
  • PT transplantable bovine embryonic kidney cells.
  • Tr transplantable bovine embryonic kidney cells.
  • TG tracheal bovine embryonic cells.
  • Hep-2 transplantable human laryngeal cancer cells.
  • HeLa are transplantable uterine cancer cells.
  • Influenza viruses H3N2
  • vesicular stomatitis Indiana strain
  • coronavirus X 343/44
  • herpes simplex virus type 1 L-2 strain
  • the antiviral effect of the drug KR2 was studied on the influenza A virus (H3 N2).
  • Aqueous solutions of KR2 in various doses were injected into the allantoic cavity of 15 chicken embryos in a volume of 0.2 ml 12 hours after the virus was injected at a working dose (100 TCD50 / 0.2 ml). Each experiment was accompanied by a test virus control at a working dose. Infected and uninfected (control) embryos were incubated at 36°C for 48 hours. Then the embryos were dissected, from which the allantoic fluid was extracted. Titration of the virus in the allantoic fluid was carried out according to the generally accepted method with 1% of erythrocytes of the 0 (1) human blood group. The protection factor (SC) was determined. The virus titer in the experimental and control groups of chicken embryos is presented in Table 12.
  • the minimum effective concentration of KR2 against influenza virus that completely inhibits virus synthesis is 0.05 mg/ml.
  • the effectiveness of KR2 decreases and is dose-dependent. This fact indicates the presence of a direct antiviral effect of the KR2 drug against the H3N2 influenza virus.
  • Study of the antiviral effect of the KR preparation on cytopathic viruses vesicular stomatitis virus, coronavirus, herpes simplex virus type 1).
  • Antiviral activity against this group of viruses was determined in the culture of the above cells.
  • the reaction was carried out as follows: 0.2 ml of the corresponding virus at a working dose (100 TCDso/0.2 ml) was added in a volume of 0.2 ml to a 2-day washed cell culture. Added 0.8 ml maintenance medium.
  • the KR preparation was administered at various doses.
  • As a control the same was done with test viruses without preparation.
  • Cells were incubated at 37°C in a thermostat. The experience was recorded for 3,5,7 days.
  • a decrease in the virus titer under the influence of the study drug by 2 1g or more compared with the control was assessed as a manifestation of antiviral activity.
  • the results of the study of the antiviral activity of the drug KP2 are presented in table 13.
  • the CTI of the drug is 1000.
  • KR2 was active against all viruses studied, while none of the comparators showed such activity.
  • the action of the drug is not associated with specific characteristics of the virus or cell culture, but affects the mechanisms common to all cells.
  • supramolecular structures also referred to as supramolecular soluble nanoparticles (SNPs), having a) a plurality of binding components, each of which has a plurality of binding regions, the plurality of binding regions including combinatorial carboxylated cobalamins; b) a plurality of nuclei that are suitable at least to provide some mechanical structure of the mentioned self-organizing supramolecular soluble systems, each of of said plurality of cores is an organic core that contains at least one core binding element adapted to bind to binding regions to form a first inclusion complex, where the core binding element comprises a combinatorial carboxylated dipyridamole, and where the first inclusion complex is a combinatorial carboxylated cobalamin with combinatorial carboxylated dipyridamole; c) a plurality of terminal components, each of which has one terminal connecting element, which binds to the remaining binding regions of one of the specified plurality of connecting components, forming a second inclusion complex, where the core binding element comprises a combin
  • Structural components and binding components of some embodiments of the present invention containing supramolecular structures can self-assemble when brought into contact with each other to form a supramolecular structure.
  • the termination components may act to occupy the binding regions of the binding components to terminate further binding when the termination components are present in sufficient quantity relative to the binding regions of the binding components.
  • a structural component contains a plurality of binding elements that link to component binding regions. binding.
  • the terminator component has a single linking element that binds to one linking region on a single linking component.
  • the supramolecular structure has at least two or more distinct terminal components.
  • the binding regions can be associated with terminal (terminal) components or structural components to form a molecular recognition pair.
  • at least one structural component, at least one connecting component, or at least one terminating component has a functional element.
  • the supramolecular structure has two or more different functional elements.
  • the invention is a composition of a substance containing supramolecular structures, also referred to as supramolecular soluble nanoparticles (SNPs), containing a mixture of combinatorial carboxylated cobalamins, containing, for example, a mixture of a succinylated derivative of cyanocobalamin, cyanocobalamin. , methyl cobalamin, hydroxycobalamin and/or cobamide.
  • SNPs supramolecular soluble nanoparticles
  • the invention is a composition of a substance containing supramolecular structures, also called supramolecular soluble nanoparticles (SNPs), containing a mixture of combinatorial carboxylated cobalamins, including succinylated hydroxycobalamin, succinylated cobamide, succinylated methylcobalamin and/or succinylated cyanocobalamin.
  • SNPs supramolecular soluble nanoparticles
  • the invention is a composition of a substance containing supramolecular structures, also called supramolecular soluble nanoparticles (SNPs), containing a mixture of supramolecular combinatorial carboxylated riboflavins, including supramolecular combinatorial succinylated derivatives of riboflavins and flavonuclears. / or flavin dinucleotide.
  • SNPs supramolecular soluble nanoparticles
  • the invention is a composition of substances containing supramolecular structures, also called supramolecular soluble nanoparticles (SNPs), containing a mixture of combinatorial carboxylated dipyridamoles containing supramolecular succinylated combinatorial derivatives of dipyridamole; supramolecular maleylated combinatorial derivatives of dipyridamole and/or carboxymethylated combinatorial derivatives of dipyridamole.
  • SNPs supramolecular soluble nanoparticles
  • the invention is a composition of a substance containing supramolecular structures, also referred to as supramolecular soluble nanoparticles (SNPs), containing supramolecular structures further containing carboxylated basic amino acids such as lysine, histidine, and arginine, and may include bis-succinylated, maleylated and carboxymethylated amino acid derivatives of carboxylated basic amino acids such as lysine, histidine and arginine.
  • SNPs supramolecular soluble nanoparticles
  • the invention is a composition in which the terminating component may include at least one of the following substances: polyethylene glycol, polymer, polypeptide or oligosaccharide, and the organic core contains at least one of the dendrimers, branched polyethyleneimine, linear polyethyleneimine, polyline , polylactide, polylactide-co-glycoside, polyanhydrides, poly-e-caprolactones, polymethyl methacrylate, poly(N-isopropylacrylamide) or polypeptides.
  • the terminating component may include at least one of the following substances: polyethylene glycol, polymer, polypeptide or oligosaccharide
  • the organic core contains at least one of the dendrimers, branched polyethyleneimine, linear polyethyleneimine, polyline , polylactide, polylactide-co-glycoside, polyanhydrides, poly-e-caprolactones, polymethyl methacrylate, poly(N-isopropylacrylamide) or poly
  • the invention is a composition in which the linking component further comprises combinatorial carboxylated derivatives of the main oligopeptide KKRKRKRKR, their carboxylated derivatives in the form of succinylated, maleylated and carboxymethylated derivatives in admixture with each other.
  • Poly-L-lysine can also be used as a binding and terminating component. Support for the original claims of embodiments of the present invention includes the following text.
  • Support claim 1 Supramolecular nanoparticles containing: a combination of nanostructures selected from the group consisting of combinatorial carboxylated cobalamins obtained from the first combinatorial synthesis; combinatorial carboxylated dipyridamoles obtained by the second combinatorial synthesis; polypeptides of basic amino acids obtained as a result of the third combinatorial synthesis, and any combination thereof.
  • supramolecular nanoparticles of claim 1 wherein the supramolecular nanoparticles have antiviral properties, wherein the supramolecular nanoparticles further comprise dynamic self-assembling soluble nanostructures, and wherein the nanostructures further comprise a plurality of binding components; many organic nuclei; and many terminating components.
  • Supramolecular nanoparticles according to claim 2, in which one of the binding components additionally includes combinatorial carboxylated cobalamins, which have a number of binding regions, while the organic cores additionally contain combinatorial carboxylated dipyridamoles, which have at least one binding element, adapted for binding to combinatorial carboxylated cobalamins, wherein the organic cores further comprise mechanical structures for dynamic self-assembling soluble nanostructures, and wherein the binding of combinatorial carboxylated cobalamins to combinatorial carboxylated dipyridamoles may further include first inclusion complexes.
  • each of the terminal components has at least one terminal binding element that binds to the remaining binding region of one of the binding components and may further contain second inclusion complexes.
  • Support according to claim 7 The supramolecular nanoparticles according to claim 1, wherein the combinatorial carboxylated cobalamins are a mixture of succinylated cyanocobalamins.
  • Support according to claim 8 Supramolecular nanoparticles according to claim 1, wherein the combinatorial carboxylated cobalamins are a mixture of succinylated methylcobalamins.
  • Support according to claim 10 Supramolecular nanoparticles according to claim 1, wherein the combinatorial carboxylated cobalamins are a mixture of succinylated cobamides.
  • Support according to claim 11 Supramolecular nanoparticles according to claim 1, wherein the combinatorial carboxylated cobalamins are selected from the group consisting of mixtures of succinylated hydroxycobalamins, mixtures of succinylated cobamides, mixtures of succinylated hydroxycobalamins, mixtures of succinylated methylcobalamins and any mixtures of succinylated cyanocobalamins, combinations thereof.
  • Support according to claim 13 The supramolecular nanoparticles according to claim 12, wherein the supramolecular combinatorial carboxylated riboflavins are supramolecular combinatorial succinylated riboflavins.
  • supramolecular nanoparticles of claim 12 wherein the supramolecular combinatorial carboxylated riboflavins are supramolecular combinatorial succinylated flavin mononucleotides.
  • Support according to claim 15 The supramolecular nanoparticles according to claim 12, wherein the supramolecular combinatorial carboxylated riboflavins are supramolecular combinatorial succinylated flavin dinucleotides.
  • the supramolecular nanoparticles of claim 5 wherein the carboxylated basic amino acids are selected from the group consisting of succinylated lysine, succinylated histidine, succinylated arginine, and any combination thereof.
  • the supramolecular nanoparticles of claim 5 wherein the carboxylated basic amino acids are selected from the group consisting of maleylated lysine, maleylated histidine, maleylated arginine, and any combination thereof.
  • the supramolecular ion particles of claim 5 wherein the carboxylated basic amino acids are selected from the group consisting of carboxymethylated lysine, carboxymethylated histidine, carboxymethylated arginine, and any combination thereof.
  • the support of claim 22 The supramolecular nanoparticles of claim 5 wherein the carboxylated basic amino acids are selected from the group consisting of carboxymethylated lysine, carboxymethylated histidine, carboxymethylated arginine, succinylated lysine, succinylated histidine, maleylated lysine, succinylated arginine, histidine, maleylated arginine, and any combination of them.
  • the support of claim 23 The supramolecular nanoparticles of claim 4, wherein the plurality of terminal components comprise at least one terminal component selected from the group consisting of polyethylene glycol, polymer, polypeptide, oligosaccharide, and any combinations thereof.
  • Support according to claim 24 Supramolecular nanoparticles according to claim 3, in which the organic cores contain at least one organic core selected from the group consisting of dendrimer, branched polyethyleneimine, linear polyethyleneimine, polylysine, polylactide, apolylactide, -co-glycoside, polyanhydride, poly-e-capro lactone, polymethyl methacrylate, poly (N-isopropylacrylamide) and polypeptide, and any combinations thereof.
  • the organic cores contain at least one organic core selected from the group consisting of dendrimer, branched polyethyleneimine, linear polyethyleneimine, polylysine, polylactide, apolylactide, -co-glycoside, polyanhydride, poly-e-capro lactone, polymethyl methacrylate, poly (N-isopropylacrylamide) and polypeptide, and any combinations thereof.
  • Support according to claim 30 Supramolecular nanoparticles according to claim 2, wherein the binder is poly-L-lysine.
  • aspects of the invention include methods for obtaining supramolecular structures by preparing a suspension of structural components, binding components and terminal (terminating) components.
  • Other aspects of the invention include selecting the ratio of the amount of structural component(s) to binding component(s) to terminal component(s) for a specific purpose, including the selection of a size intended for supramolecular structures.
  • the structural component(s), the linking component(s), and the terminal component(s) may be capable of self-assembly into preferred supramolecular structures of substantially predetermined size.
  • supramolecular structure refers to, for example, the values of supramolecular assembly and supramolecular structure.
  • a supramolecular assembly can be defined as a complex of molecules held together by non-covalent bonds.
  • a supramolecular assembly may simply consist of two molecules (eg, a DNA double helix or an inclusion junction) or a larger complex(s) of molecules forming, for example, a sphere, rod, or sheet, as particles, nanoparticles, or discrete particles.
  • Micelles, liposomes, and biological membranes are also examples of some types of supramolecular assemblies.
  • the sizes of supramolecular assemblies are expected to have a wide possible range, for example, for embodiments of the present invention, the range from about 5 nanometers to about 10 microns.
  • the present description discloses ranges of sizes of supramolecular assemblies and structures individually or in combination of supramolecular structures (assemblies) forming nanoparticles.
  • the general field of supramolecular chemistry is the field of chemistry concerned with chemical systems that are composed of a discrete number of molecules.
  • the strength of the forces responsible for the spatial organization of the system varies from weak intermolecular forces, electrostatic charge or hydrogen bonding, to strong covalent bonds, provided that the strength of the electronic interaction remains small compared to the energy parameters of the component.
  • supramolecular chemistry is additionally concerned with weaker and reversible non-covalent interactions between molecules, which therefore produce combinations of small molecules for supermolecules or supramolecular assemblies, in which the number of supramolecular structures is conceived by the inventor and disclosed in the description and may be a calculated or estimated number using the calculations of combinatorial chemistry and combinatorial mathematics, which are disclosed in the present description.
  • Supramolecular assemblies form and can have average lifetimes maintained by hydrogen bonds, metal coordination, hydrophobic forces, van der Waals forces, pi-pi interactions, and electrostatic effects between small molecules that make up combinatorial supramolecular assemblies.
  • Supramolecular chemistry is also concerned with dynamic (spontaneous, energy dependent, entropy and thermodynamic processes) molecular self-assembly, molecular folding, molecular recognition, host-guest chemistry, mechanically interconnected molecular architectures, and dynamic covalent chemistry.
  • the foundations of these ideas about supramolecular science are based on the teachings of the prior art, as disclosed in the Background of the Invention section.
  • the concept of "supramolecular soluble systems” includes supramolecular soluble systems as a whole and includes the solubility of their components, as well as the solubility of the assembly and its components at various stages of the assembly process, forming supramolecular assemblies (structures).
  • the nanoparticle value includes the ultrafine particle and/or discrete particle values.
  • the nanoparticle in some embodiments of the present invention has the largest size, which is from 1 nanometer to 10,000 nanometers. Structural, binding and terminating components self-organize into supramolecular structures having a substantially predetermined size.
  • the predetermined size is preferably at least about 10 nm and less than about 800 nm (nanometers).
  • the specified size is from about 5 nm to 2000 nm.
  • the specified size is at least about 20 nm and less than about 400 nm (nanometers).
  • the average absolute/maximum size of a hydrated nanoparticle can be measured in a liquid by direct laser scanning (DLS) using a Malvern Instruments Zetasizer for sizing.
  • Optical and/or X-ray technology or testing using nanometer and/or micron filter membrane filtration methods known in the prior art may also be useful in determining the average size or relative size of nanoparticles.

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Abstract

Selon l'invention, des nanoparticules supramoléculaires comportent des cobalamines carboxylées combinatoires obtenues suite à une première synthèse combinatoire, des dipyridamoles carboxylés obtenus par une deuxième synthèse combinatoire, des polypeptides d'acides aminés principaux obtenus suite à une troisième synthèse combinatoire, ou leurs combinaison. Ces nanoparticules supramoléculaires consistent en des nanostructures solubles dynamiques à organisation automatique qui possèdent une pluralité de composants de liaison, des noyaux organiques et des composants terminaux. Les composants de liaison comprennent des cobalamines carboxylées combinatoires avec des sections de liaison. Les noyaux organiques comprennent du dipyridamole carboxylé adapté pour se lier à des cobalamines carboxylées combinatoires de sorte que les noyaux organiques puissent produire une structure mécanique pour des nanostructures solubles à organisation automatique et un premier type de complexes d'inclusion. Ces nanoparticules supramoléculaires comprennent des composants terminaux comprenant au moins un élément de liaison terminal capable de se lier à une région de liaison résiduelle des composants de liaison, lesquels permettent de produire un second type de complexes d'inclusion.
PCT/RU2021/000447 2021-10-19 2021-10-19 Systèmes supramoléculaires à base de nanostructures dynamiques à organisation automatique possédant des propriétés antivirales WO2023068958A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010099466A2 (fr) * 2009-02-26 2010-09-02 The Regents Of The University Of California Approche supramoléculaire pour la préparation de nanoparticules à taille réglable
WO2018237109A1 (fr) * 2017-06-23 2018-12-27 Yale University Nanomatériaux présentant une efficacité améliorée d'administration de médicament
EP2861256B1 (fr) * 2012-06-15 2019-10-23 The Brigham and Women's Hospital, Inc. Compositions pour le traitement du cancer et leurs procédés de préparation
WO2020092884A2 (fr) * 2018-11-02 2020-05-07 The Regents Of The University Of California Nanoparticules supramoléculaires réticulées pour la libération contrôlée de médicaments antifongiques et de stéroïdes - une nouvelle approche thérapeutique contre l'onychomycose et les chéloïdes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010099466A2 (fr) * 2009-02-26 2010-09-02 The Regents Of The University Of California Approche supramoléculaire pour la préparation de nanoparticules à taille réglable
EP2861256B1 (fr) * 2012-06-15 2019-10-23 The Brigham and Women's Hospital, Inc. Compositions pour le traitement du cancer et leurs procédés de préparation
WO2018237109A1 (fr) * 2017-06-23 2018-12-27 Yale University Nanomatériaux présentant une efficacité améliorée d'administration de médicament
WO2020092884A2 (fr) * 2018-11-02 2020-05-07 The Regents Of The University Of California Nanoparticules supramoléculaires réticulées pour la libération contrôlée de médicaments antifongiques et de stéroïdes - une nouvelle approche thérapeutique contre l'onychomycose et les chéloïdes

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