Inhibition of a tripartite vor protein complex in multicellular organisms

{
  "publication_number": "US2026102391A1",
  "country": "US",
  "kind": "A1",
  "title": "Inhibition of a tripartite vor protein complex in multicellular organisms",
  "abstract": "The present disclosure relates generally to methods of inhibiting a tripartite VAP-A, ORP3 and Rab7 (VOR) protein complex in multicellular organisms, to methods of identifying agents which inhibit such complex and to the medical use of those agents. Inhibition of the VOR complex causes interference with at least one mechanism of intercellular communication, wherein the intercellular communication is mediated by receptor-ligand interaction and/or EVs, and viral infection involving the transport of endocytosed biomaterials to the nucleus of recipient cells.",
  "claims": [
    "1. A method for identifying an agent which inhibits the tripartite VOR protein complex, wherein the method comprises contacting at least one eukaryotic cell having the tripartite VOR protein complex with the chemical agent under conditions suitable for binding, and detecting the integrity of the tripartite VOR protein complex and/or consequence of loss of the tripartite VOR protein complex. 2. A method according to claim 1, for identifying a VOR protein complex inhibitor chemical agent for use as a pharmaceutical agent or a lead compound, wherein the method comprises screening one or more chemical agents and determining their ability to inhibit the tripartite VOR protein complex. 3. A method according to claim 1, wherein the method comprises determining the specific activity of the identified agent or agents for inhibiting the tripartite VOR protein complex, and wherein the method further comprises: measuring the integrity of the tripartite VOR protein complex; determining the consequences of loss of the tripartite VOR protein complex in response to: a) presence/absence of the chemical agent; and b) external stimuli, wherein the external stimuli include at least one of extracellular vesicles (EVs), viruses, ligands. 4. A method according to claim 2, wherein the method for screening the identified chemical agent comprises: (a) infecting the recipient cells in well plates with at least one of VSV-G-pseudotyped HIV- 1 NL4-3 Gag-iGFP deltaEnv Non-Infectious Molecular Clone or similar fluorescent viruses; (b) contacting at least one identified chemical agent with the recipient cells for identifying the one or more lead compounds which strongly decreases fluorescence of a recipient cell population compared to a mock control, wherein the identified chemical agent is derived from screening of small molecule libraries and selected compounds associated with the recipient cell; and (c) adding a vital dye to exclude the recipient cells that are non-selectively damaged by the one or more lead compounds before the automatic imaging. 5. A method according to claim 3, wherein the method for screening the identified chemical agent further comprises: (a) isolating EVs from any cell line, which has been engineered to express Cre recombinase protein fused in-frame to CD9 or to another protein that gets transported into the nucleus upon internalization of EVs by recipient cell; (b) adding the modified EVs that contain the Cre recombinase-CD9 fusion protein to any cell lines harboring cre-loxP sites, which would drive after recombination the expression of fluorescent reporter gene; (c) pre-incubation of recipient cells with chemical agents that would block and/or interfere with VOR complex activity, i.e. leading to the inhibition of nuclear transfer of EV-derived materials notably Cre recombinase-CD9 fusion protein. With this setting, we will screen for compounds that block the EV-mediated activation of fluorescent reporter protein by recipient cells. 6. A method according to claim 1, wherein the method includes using the tripartite VOR protein complex as a molecular target for the screening of chemical agents for their ability to inhibit the tripartite VOR protein complex. 7. A method according to claim 1, wherein the recipient cell is carcinogenic, wherein the carcinogenic cell is at least one of a kidney carcinoma, a bladder carcinoma, an endometrial carcinoma or a head and neck carcinoma, wherein the recipient cell is at least one of a stromal cell, an epithelia cell, a neuron, a cardiac cell, a pancreatic cell, a renal cell, a cone cell and an alveolar macrophage cell, wherein the recipient cell is infectious external stimuli, wherein the external stimulus is a virus, and wherein the virus is HIV-1. 8. A tripartite VOR protein complex inhibitor agent for use in medicine. 9. An agent for use according to claim 8, wherein such inhibition causes interference with at least one mechanism of: (a) intercellular communication, wherein the intercellular communication is mediated by receptor-ligand interaction and/or EVs; and (b) viral infection involving the transport of endocytosed biomaterials to the nucleus of recipient cells. 10. An agent for use according to claim 8, for use in treatment or prevention of a disease or condition in which the tripartite VOR protein complex is implicated. 11. An agent for use according to claim 9 for use in the treatment or prevention of cancer and cancer metastasis, and wherein the cancer includes at least one of a kidney carcinoma, a bladder carcinoma, an endometrial carcinoma, head and neck cancer. 12. An agent for use according to claim 9 for use in the treatment or prevention of an infectious disease, wherein the disease is caused by a virus, and wherein the virus is HIV-1. 13. An agent for use according to claim 9, for use in the treatment of at least one of a neurodegenerative disease, a ventricular hypertrophy, a type I diabetes, a type II disease, a macular degeneration and a lung disease. 14. An agent for use according to claim 9, wherein the agent is selected from Itraconazole or an Itraconazole analogue or salts thereof 15. A compound for use according to claim 14, wherein the Itraconazole analogue is an analogue in which the secbutyl chain of the Itraconazole has been replaced by another straight or branched"
  ],
  "description_excerpt": "The present disclosure relates generally to methods of inhibiting a tripartite VAP-A, ORP3 and Rab7 (VOR) protein complex in multicellular organisms, to methods of identifying agents which inhibit such complex and to the medical use of those agents. The invention further relates to an inhibitor of a tripartite VAP-A, ORP3 and Rab7 (VOR) protein complex for use in medicine. The present disclosure further relates to the use of Itraconazole or an Itraconazole analogue for the prevention or treatment of carcinoma and infectious diseases. Specifically, the present disclosure relates to Itraconazole or an Itraconazole analogue or salts thereof for use in inhibiting a tripartite VAP-A, ORP3 and Rab7 (VOR) protein complex in multicellular organisms. The present disclosure further relates to the use of the aforesaid compound to execute the aforesaid method.\n\nCancer and certain viral diseases (such as, HIV) are among the leading causes of fatal illness, with millions of deaths due to such diseases worldwide.\n\nDespite the rapid advances in biomedical sciences, the practices employed for the treatment of such fatal diseases are still inadequate in many cases. Traditionally, many immunotherapeutic strategies are being explored to combat cancer, viral infections and age-related diseases. Treatments based on chemotherapy may be employed for curing Cancer. One approach is the inhibition of the process of cell multiplication, killing dividing cells by mutilating the control center (namely, nucleus) of such dividing cells or by interrupting the chemical processes involved in cell division.",
  "cpc": [
    "A61K 31/496",
    "A61P 31/18",
    "A61P 35/00",
    "G01N 2500/02",
    "G01N 33/5035",
    "G01N 33/6845"
  ],
  "inventors": [
    "Aurelio LORICO",
    "Denis CORBEIL",
    "Mark Santos",
    "Germana Rappa"
  ],
  "filing_date": "2025-12-15",
  "publication_date": "2026-04-16",
  "priority_date": "2018-06-27",
  "application_number": "US-202519419422-A",
  "cited_by_count": 0
}