# US 11,111,296 B2 · Compositions and methods for treating cardiac dysfunction > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,111,296 B2 - Document ID: US11111296B2 - Status: Granted - Kind: B2 - Application number: 16/061,652 - Filed: 2016-12-13 - Published: 2018-12-20 - Granted: 2021-09-07 - Earliest claimed: 2015-12-14 - Assignees: The Broad Institute, Inc.; Dana-Farber Cancer Institute, Inc. - Applicants: The Broad Institute, Inc.; Dana-Farber Cancer Institute, Inc. - Inventors: David K. Thomas; Todd R. Golub - Web page: https://patentgrep.com/patent/US11111296B2 ## CPC - C07K 16/2803: {against the immunoglobulin superfamily} - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - G16C 10/00: Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like - G16C 20/00: Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures - G16C 20/20: Identification of molecular entities, parts thereof or of chemical compositions - G16C 20/50: Molecular design, e.g. of drugs - G16C 20/60: In silico combinatorial chemistry - G16C 20/62: Design of libraries - G16C 20/64: Screening of libraries - A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)} - A61K 2039/505: {comprising antibodies} - C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract The invention provides compositions and methods for treating cardiac dysfunction, particularly cachexia-associated or RAGE-associated cardiac dysfunction, using an anti-RAGE agent. The invention also provides compositions and methods for identifying therapeutic agents useful for disrupting (slowing, reducing, reversing, or preventing). The methods comprise designing or identifying agents that bind to functional sites identified on the RAGE polypeptide, wherein binding of agents to the functional site(s) inhibit RAGE-mediated cachetogenic signaling. ## Claims ### Claim 1 A method for synthesizing a candidate compound that binds to a site on a RAGE polypeptide, the method comprising: (a) accessing, by a computer, a three-dimensional structure of a RAGE polypeptide having at least one atomic coordinate, or surrogate thereof, from Protein Data Bank (PDB) ID: 4LP4 for each of the amino acid residues 23-54 or for each of the amino acid residues 25, 54, 59, 61, 91, 92, 94, 96, 98, 114, 116, 150, 151, 152, 154, 175, 177, 178, 179, 186, 213 and 216 of the RAGE polypeptide, or having atomic coordinates that have a root mean square deviation of the coordinates of less than 3 angstroms; (b) screening, by the computer, each chemical compound fragment in a set of chemical compound fragments having a three dimensional structure that interacts with the three-dimensional structure of the RAGE polypeptide accessed in step (a) by determining a subset of the chemical compound fragments in the set of the chemical compound fragments that have one or more different orientations of the three-dimensional structure of the subset of the chemical compound fragments that are complementary to a binding site of the three-dimensional structure of the RAGE polypeptide to structurally model a specific interaction of the with the binding site on the RAGE polypeptide; (c) selecting, by the computer, a candidate compound structure comprising a selection of chemical compound fragments in the subset of the chemical compound fragments, wherein the selection of chemical compound fragments (i) specifically interact with a binding site of the RAGE polypeptide based on step (b), and/or (ii) possesses one or both of steric fit and electrostatic complementarity to the binding site of the RAGE polypeptide, and wherein the candidate compound structure defines a molecule having sufficient surface complementary to the RAGE polypeptide to specifically bind to the site on the RAGE polypeptide in an aqueous solution; (d) assembling, by the computer, the subset of the chemical compound fragments of the candidate compound structure into a single compound structure; and (e) synthesizing the single compound structure that binds to a site on a RAGE polypeptide so as to regulate RAGE-mediated cachetogenic activity. ### Claim 2 (depends on 1) The method of claim 1, further comprising the step of (f) assaying binding of the compound to a RAGE polypeptide in an in vitro, in vivo, or ex vivo assay. ### Claim 3 (depends on 2) The method of claim 2, further comprising the step of (g) assaying inhibition of cachexia or loss of myosin heavy chain by the compound in a functional cachexia assay. ### Claim 4 (depends on 1) The method of claim 1, wherein the structure of the candidate compound is designed de novo by assembling the subset of the chemical compound fragments of the chemical compound into a single compound structure. ### Claim 5 (depends on 3) The method of claim 3, further comprising the step of (h) modifying the candidate compound based upon the positioning, alignment, and interactions between the candidate compound and one or more amino acids comprising the site. ### Claim 6 (depends on 3) The method of claim 3, wherein the results of the assay of step (f) or step (g) provide further structure related binding information such that other candidate compounds are selected for evaluation. ### Claim 7 (depends on 1) The method of claim 1, wherein the candidate compound structure or the subset of the chemical compound fragments thereof are screened from a virtual compound library.