# US 2013/0280271 A1 · Inhibiting the integration of retrovirus dna into host cell dna by inhibiting integrase reaching dimer formation > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2013/0280271 A1 - Document ID: US20130280271A1 - Status: Published application - Kind: A1 - Application number: 13/923,494 - Filed: 2013-06-21 - Published: 2013-10-24 - Earliest claimed: 2010-12-23 - Assignees: Institute For Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center ("Fox Chase - Applicants: Institute for Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center ("Fox Chase - Inventors: Anna Marie Skalka; Mark Andrake; Ravi Shankar Bojja - Web page: https://patentgrep.com/patent/US20130280271A1 ## CPC - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - C12N 9/22: Ribonucleases {[RNase]; Deoxyribonucleases [DNase]} - C12Q 1/18: Testing for antimicrobial activity of a material - C12Q 1/34: involving hydrolase - C07K 16/1143: {Gag-pol proteins, e.g. p17or p24} - C12N 2740/11022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes - C12N 2740/16211: concerning HIV gagpol - C12N 2740/16222: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes - G01N 2333/161: gag-pol, e.g. p55, p24/25, p17/18, p.7, p6, p66/68, p51/52, p31/34, p32, p40 - G01N 2333/922: Ribonucleases (RNAses); Deoxyribonucleases (DNAses) - 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) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES - 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) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract Methods to inhibit the formation of retrovirus integrase reaching dimers, to dissociate retrovirus integrase reaching dimers, and to stabilize retrovirus integrase reaching dimers in a conformation in which retrovirus DNA-to host cell DNA integration activity of the integrase is inhibited are provided. Methods for treating a retrovirus infection, which target retrovirus integrase reaching dimer formation and/or stability are also provided. ## Claims ### Claim 1 A method for inhibiting retrovirus integrase-mediated insertion of retrovirus DNA into the DNA of a host cell infected with a retrovirus and expressing retrovirus integrase monomers encoded by the retrovirus, comprising inhibiting the formation of a reaching dimer by the retrovirus integrase monomers, or stabilizing a formed reaching dimer in a conformation that inhibits the capability of the reaching dimer to bind to substrate DNA in the host cell such that retrovirus DNA insertion activity of the retrovirus integrase is inhibited. ### Claim 2 (depends on 1) The method of claim 1, wherein the retrovirus is selected from the group consisting of avian sarcoma virus, human immunodeficiency virus, and human T-lymphotropic virus 1. ### Claim 3 (depends on 1) The method of claim 1, wherein the retrovirus comprises human immunodeficiency virus, and the host cell comprises a human T lymphocyte or a human macrophage. ### Claim 4 (depends on 1) The method of claim 1, wherein inhibiting the formation of the reaching dimer comprises contacting the host cell with a compound or biomolecule that inhibits the formation of a reaching dimer in an amount effective to inhibit the formation of the reaching dimer by the retroviral integrase. ### Claim 5 (depends on 1) The method of claim 1, wherein inhibiting the formation of the reaching dimer comprises inhibiting intermolecular interactions between amino acids in the C-terminal domain of a first retrovirus integrase monomer and amino acids in the C-terminal domain of a second retrovirus integrase monomer that mediate the formation of the reaching dimer, inhibiting the intermolecular interactions between amino acids in the N-terminal domain of a first retrovirus integrase monomer and amino acids in the C-terminal domain of a second retrovirus integrase monomer that mediate the formation of the reaching dimer, inhibiting the intermolecular interactions between amino acids in the N-terminal domain of a first retrovirus integrase monomer and amino acids in the N-terminal domain of a second retrovirus integrase monomer that mediate the formation of the reaching dimer, or combinations thereof. ### Claim 6 (depends on 5) The method of claim 5, wherein the retrovirus is avian sarcoma virus, and the intermolecular interactions between amino acids in the C-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer are selected from the group consisting of the intermolecular interactions between the tryptophan at position 259 of the first retrovirus integrase monomer and the tryptophan at position 259 of the second retrovirus integrase monomer, the intermolecular interactions between the tyrosine at position 246 of the first retrovirus integrase monomer and the tyrosine at position 246 of the second retrovirus integrase monomer, the intermolecular interactions between one or more of the arginine at position 244, the glycine at position 245, and the tyrosine at position 246 of the first retrovirus integrase monomer and one or more of the arginine at position 244, the glycine at position 245, and the tyrosine at position 246 of the second retrovirus integrase monomer, and combinations thereof. ### Claim 7 (depends on 5) The method of claim 5, wherein the retrovirus is human immunodeficiency virus, and the intermolecular interactions between amino acids in the C-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer are selected from the group consisting of the intermolecular interactions between the tryptophan at position 243 of the first retrovirus integrase monomer and the tryptophan at position 243 or the lysine at position 244 of the second retrovirus integrase monomer, the intermolecular interactions between the lysine at position 236 of the first retrovirus integrase monomer and the glutamic acid at position 212 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 246 of the first retrovirus integrase monomer and the lysine at position 211 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 246 of the first retrovirus integrase monomer and the lysine at position 240 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 246 of the first retrovirus integrase monomer and the lysine at position 264 of the second retrovirus integrase monomer, the intermolecular interactions between the lysine at position 264 of the first retrovirus integrase monomer and the aspartic acid at position 279 of the second retrovirus integrase monomer, the intermolecular interactions between the lysine at position 264 of the first retrovirus integrase monomer and the aspartic acid at position 286 of the second retrovirus integrase monomer, the intermolecular interactions between the lysine at position 264 of the first retrovirus integrase monomer and the glutamic acid at position 287 of the second retrovirus integrase monomer, the intermolecular interactions between the lysine at position 264 of the first retrovirus integrase monomer and the aspartic acid at position 288 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 287 of the first retrovirus integrase monomer and the lysine at position 188 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 287 of the first retrovirus integrase monomer and the lysine at position 211 of the second retrovirus integrase monomer, and combinations thereof. ### Claim 8 (depends on 5) The method of claim 5, wherein the retrovirus is human immunodeficiency virus, and the intermolecular interactions between amino acids in the C-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer are selected from the group consisting of the intermolecular interactions between the lysine at position 236 of the first retrovirus integrase monomer and the glutamic acid at position 212 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 246 of the first retrovirus integrase monomer and the lysine at position 240 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 246 of the first retrovirus integrase monomer and the lysine at position 264 of the second retrovirus integrase monomer, and combinations thereof. ### Claim 9 (depends on 5) The method of claim 5, wherein the retrovirus is avian sarcoma virus, and the intermolecular interactions between amino acids in the N-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer are selected from the group consisting of the intermolecular interactions between the serine at position 20 of the first retrovirus integrase monomer and the tryptophan at position 213 of the second retrovirus integrase monomer, the intermolecular interactions between the asparagine at position 24 of the first retrovirus integrase monomer and the arginine at position 214 of the second retrovirus integrase monomer, the intermolecular interactions between the serine at position 26 of the first retrovirus integrase monomer and the arginine at position 214 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamine at position 28 of the first retrovirus integrase monomer and the threonine at position 216 of the second retrovirus integrase monomer, the intermolecular interactions between the arginine at position 31 of the first retrovirus integrase monomer and the arginine at position 244 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamine at position 28 of the first retrovirus integrase monomer and the serine at position 262 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 32 of the first retrovirus integrase monomer and the arginine at position 263 of the second retrovirus integrase monomer, and combinations thereof. ### Claim 10 (depends on 5) The method of claim 5, wherein the retrovirus is human immunodeficiency virus, and the intermolecular interactions between amino acids in the N-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer are selected from the group consisting of the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the aspartic acid at position 116 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 157 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 170 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 212 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the aspartic acid at position 229 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 246 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 270 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the aspartic acid at position 279 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 287 of the second retrovirus integrase monomer, the intermolecular interactions between the aspartic acid at position 6 of the first retrovirus integrase monomer and the lysine at position 159 of the second retrovirus integrase monomer, the intermolecular interactions between the aspartic acid at position 6 of the first retrovirus integrase monomer and the lysine at position 188 of the second retrovirus integrase monomer, the intermolecular interactions between the aspartic acid at position 6 of the first retrovirus integrase monomer and the lysine at position 215 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 11 of the first retrovirus integrase monomer and the lysine at position 215 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 13 of the first retrovirus integrase monomer and the lysine at position 240 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 35 of the first retrovirus integrase monomer and the lysine at position 264 of the second retrovirus integrase monomer, and combinations thereof. ### Claim 11 (depends on 5) The method of claim 5, wherein the retrovirus is human immunodeficiency virus, and the intermolecular interactions between amino acids in the N-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer are selected from the group consisting of the intermolecular interactions between the glutamic acid at position 35 of the first retrovirus integrase monomer and the lysine at position 264 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 13 of the first retrovirus integrase monomer and the lysine at position 24 0 of the second retrovirus integrase monomer, the intermolecular interactions between the aspartic acid at position 6 of the first retrovirus integrase monomer and the lysine at position 215 of the second retrovirus integrase monomer, and combinations thereof. ### Claim 12 (depends on 5) The method of claim 5, wherein the retrovirus is avian sarcoma virus, and the intermolecular interactions between amino acids in the N-terminal domain of the first retrovirus integrase monomer and amino acids in the N-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer comprise the intermolecular interactions between the asparagine at position 24 of a first retrovirus integrase monomer and the arginine at position 53 of a second retrovirus integrase monomer. ### Claim 13 (depends on 5) The method of claim 5, wherein the retrovirus is human immunodeficiency virus, and the intermolecular interactions between amino acids in the N-terminal domain of the first retrovirus integrase monomer and amino acids in the N-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer are selected from the group consisting of the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 10 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 11 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 13 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 35 of the second retrovirus integrase monomer, and combinations thereof. ### Claim 14 A method for treating a retrovirus infection in a subject in need thereof, comprising administering to the subject a compound or antibody capable of inhibiting the formation of a retrovirus integrase reaching dimer in an amount effective to inhibit the formation of the reaching dimer by monomers of a retrovirus integrase in a cell of the subject infected with the retrovirus such that retrovirus DNA insertion activity of the retrovirus integrase is inhibited. ### Claim 15 (depends on 14) The method of claim 14, wherein the subject is a human being, the retrovirus is human immunodeficiency virus, and the compound or antibody inhibits the formation of the reaching dimer by inhibiting intermolecular interactions between amino acids in the C-terminal domain of a first retrovirus integrase monomer and amino acids in the C-terminal domain of a second retrovirus integrase monomer that mediate the formation of the reaching dimer, inhibits the intermolecular interactions between amino acids in the N-terminal domain of a first retrovirus integrase monomer and amino acids in the C-terminal domain of a second retrovirus integrase monomer that mediate the formation of the reaching dimer, inhibits the intermolecular interactions between amino acids in the N-terminal domain of a first retrovirus integrase monomer and amino acids in the N-terminal domain of a second retrovirus integrase monomer that mediate the formation of the reaching dimer, or combinations thereof. ### Claim 16 (depends on 15) The method of claim 15, wherein the intermolecular interactions between amino acids in the C-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer comprise the intermolecular interactions between the lysine at position 236 of the first retrovirus integrase monomer and the glutamic acid at position 212 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 246 of the first retrovirus integrase monomer and the lysine at position 240 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 246 of the first retrovirus integrase monomer and the lysine at position 264 of the second retrovirus integrase monomer, or a combination thereof. ### Claim 17 (depends on 15) The method of claim 15, wherein the intermolecular interactions between amino acids in the N-terminal domain of the first retrovirus integrase monomer and amino acids in the C-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer comprise the intermolecular interactions between the glutamic acid at position 35 of the first retrovirus integrase monomer and the lysine at position 264 of the second retrovirus integrase monomer, the intermolecular interactions between the glutamic acid at position 13 of the first retrovirus integrase monomer and the lysine at position 240 of the second retrovirus integrase monomer, the intermolecular interactions between the aspartic acid at position 6 of the first retrovirus integrase monomer and the lysine at position 215 of the second retrovirus integrase monomer, or a combination thereof. ### Claim 18 (depends on 15) The method of claim 15, wherein the intermolecular interactions between amino acids in the N-terminal domain of the first retrovirus integrase monomer and amino acids in the N-terminal domain of the second retrovirus integrase monomer that mediate the formation of the reaching dimer comprise the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 10 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 11 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 13 of the second retrovirus integrase monomer, the intermolecular interactions between the phenylalanine at position 1 of the first retrovirus integrase monomer and the glutamic acid at position 35 of the second retrovirus integrase monomer, or a combination thereof. ### Claim 19 (depends on 15) The method of claim 15, wherein the cell comprises a T lymphocyte or a macrophage. ### Claim 20 A method for treating a retrovirus infection in a subject in need thereof, comprising administering to the subject a compound or antibody capable of stabilizing a conformation of a formed retrovirus integrase reaching dimer in an amount effective to stabilize the reaching dimer in a cell of the subject infected with the retrovirus in a conformation that inhibits the capability of the reaching dimer to bind to substrate DNA.