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CN-122003248-A - Low density lipoprotein receptor modulation for the treatment of infections

CN122003248ACN 122003248 ACN122003248 ACN 122003248ACN-122003248-A

Abstract

Compositions and methods for preventing or treating a Crimedes-Congo hemorrhagic fever virus (CCHFV) infection, or for preventing or treating Crimedes-Congo hemorrhagic fever, are provided. The method comprises administering to a subject infected with a virus or at risk of infection an agent that reduces expression or activity of LDLR, or inhibits interaction between Low Density Lipoprotein Receptor (LDLR) and Gc glycoprotein (Gc) of CCHFV in the subject.

Inventors

  • WANG YANDIE
  • XU ZHISHENG

Assignees

  • 中国科学院武汉病毒研究所

Dates

Publication Date
20260508
Application Date
20231017

Claims (20)

  1. 1. A method for preventing or treating a crimia-congo hemorrhagic fever virus (CCHFV) infection, or for preventing or treating a crimia-congo hemorrhagic fever in a subject, comprising administering to the subject an agent that reduces the expression or activity of LDLR, or inhibits the interaction between Low Density Lipoprotein Receptor (LDLR) and Gc glycoprotein (Gc) of CCHFV in the subject.
  2. 2. The method of claim 1, wherein the agent is selected from the group consisting of: (a) Soluble LDLR proteins; (b) An anti-LDLR antibody or antigen-binding fragment; (c) An anti-Gc antibody or antigen-binding fragment; (d) Small molecule inhibitors of LDLR or Gc; (e) Inhibitory RNAs that inhibit LDLR expression; (f) A gene editing agent that reduces LDLR expression or activity; (g) Rapamycin; (h) A Liver X Receptor (LXR) agonist, LXR protein or a polynucleotide encoding LXR protein; (i) Retinol X Receptor (RXR) agonists, RXR proteins or polynucleotides encoding RXR proteins; (j) ZFP36 loop refers to a protein-like 1 (ZFP 36L 1) agonist, ZFP36L1 protein, or a polynucleotide encoding ZFP36L1 protein; (k) ZFP36 loop refers to a protein-like 2 (ZFP 36L 2) agonist, ZFP36L2 protein, or a polynucleotide encoding ZFP36L2 protein; (l) Progestogen and an AdipoQ receptor family member 3 (PAQR 3) agonist, a PAQR3 protein, or a polynucleotide encoding a PAQR3 protein; (m) a proprotein convertase subtilisin/kexin type 9 (PCSK 9) agonist, a PCSK9 protein, or a polynucleotide encoding a PCSK9 protein; (n) Low Density lipoproteins, and (O) an agent or molecule or combination thereof that directly or indirectly causes down-regulation of the level of LDLR or its soluble extracellular domain or CCHFV binding activity.
  3. 3. The method of claim 2, wherein the agent is a soluble LDLR protein, preferably comprising no transmembrane domain of LDLR protein and comprising at least one LDLR type a repeat in a Ligand Binding Domain (LBD).
  4. 4. The method of claim 3, wherein the soluble LDLR protein comprises at least LDLR type a repeat 1, LDLR type a repeat 2, LDLR type a repeat 3, LDLR type a repeat 4, LDLR type a repeat 5, LDLR type a repeat 6, or LDLR type a repeat 7.
  5. 5. The method of claim 3, wherein the soluble LDLR protein further comprises an IgG Fc domain.
  6. 6. The method of claim 2, wherein the agent is an anti-LDLR antibody or antigen-binding fragment which preferentially binds at least one LDLR type a repeat in a Ligand Binding Domain (LBD).
  7. 7. The method of claim 6, wherein the anti-LDLR antibody or antigen-binding fragment does not bind to the EGF-like domain of LDLR protein.
  8. 8. The method of claim 2, wherein the agent is an anti-Gc antibody or antigen-binding fragment.
  9. 9. The method of claim 2, wherein the agent is a small molecule inhibitor of LDLR or Gc.
  10. 10. The method of claim 2, wherein the agent is an inhibitory RNA that inhibits LDLR expression.
  11. 11. The method of claim 10, wherein the inhibitory RNA is selected from the group consisting of miRNA, siRNA, shRNA, piRNA, asRNA and antisense RNA.
  12. 12. The method of claim 2, wherein the agent is a gene editing agent that reduces LDLR expression or activity.
  13. 13. The method of claim 12, wherein the gene editing agent comprises a CRISPR/Cas agent, a TALEN agent, or a zinc finger nuclease.
  14. 14. The method of claim 2, wherein the agent is rapamycin.
  15. 15. The method of claim 2, wherein the agent is a Liver X Receptor (LXR) agonist, LXR protein, or a polynucleotide encoding LXR protein.
  16. 16. The method of claim 15, wherein the LXR agonist is selected from the group consisting of oxysterol, hypocholesterolemic amide, T0901317, GW3965, and N, N-dimethyl-3 β -hydroxy-cholestyramide (DMHCA).
  17. 17. The method of claim 16, wherein the oxy-cholesterol is selected from the group consisting of 22 (R) -hydroxycholesterol, 24 (S) -hydroxycholesterol, 27-hydroxycholesterol, and cholesteryl acid.
  18. 18. The method of claim 2, wherein the agent is a Retinol X Receptor (RXR) agonist, a RXR protein, or a polynucleotide encoding a RXR protein.
  19. 19. The method according to claim 18, wherein the RXR agonist is 9-cis-13, 14-dihydroretinoic acid.
  20. 20. The method of claim 2, wherein the agent is a protein selected from the group consisting of Liver X Receptor (LXR), retinol X Receptor (RXR), ZFP36 ring finger protein-like 1 (ZFP 36L 1), ZFP36 ring finger protein-like 2 (ZFP 36L 2), progestogen and AdipoQ receptor family member 3 (PAQR 3), and proprotein convertase subtilisin/kexin type 9 (PCSK 9), or a polynucleotide encoding the protein.

Description

Low density lipoprotein receptor modulation for the treatment of infections Background Crimedes-Congo hemorrhagic fever virus (CCHFV) is a widely distributed tick-borne human and animal co-virus belonging to the genus Adenoviral (Orthonairovirus) of the family Endocarpiidae (Nairoviridae) of the order Bunyaviridae (Bunyavirales), which has been reported in more than 30 countries in Africa, europe and Asia. Although CCHFV infection is asymptomatic in most vertebrates, it can lead to severe viral hemorrhagic fever in humans with mortality rates of up to 40% in established cases. Currently, there is no approved vaccine or specific anti-CCHFV drug, and thus there is limited treatment options for CCHFV infection. Because of their great public health risks and lack of countermeasures, CCHFV has been listed for many years by the World Health Organization (WHO) as a priority pathogen developed in the public health emergency setting. CCHFV has a negative-sense three-segment RNA genome consisting of S, M and L segments, encoding Nucleoprotein (NP), glycoprotein Precursor (GPC) and RNA-dependent RNA polymerase (RdRP), respectively. M-encoded GPC is co-translationally cleaved by cellular proteases to yield two structural glycoproteins Gc and Gn, and three non-structural protein mucins, GP38 and NSm. The Gc and Gn glycoproteins form locally ordered heterodimeric lattices on the viral surface responsible for binding to cellular receptors and subsequent fusion of the viral envelope with the host cell membrane. Gc is a class II membrane protein and is also the only known target for CCHFV neutralizing antibodies. There is a need to develop effective therapies to prevent and treat CCHFV infection. Disclosure of Invention The entry of CCHFV into target cells has been demonstrated by receptor-mediated endocytosis. The polysomes are sites of virus-endosomal membrane fusion. However, the cellular receptors for CCHFV infection have been unknown, which greatly hampers understanding of CCHFV-host interactions and development of effective therapeutic strategies for CCHF. The inventors of the present invention have thus identified that Low Density Lipoprotein Receptor (LDLR) is an important entry receptor for CCHFV infection. Gene knockout of LDLR impairs viral infection in a variety of CCHFV-susceptible human, monkey and mouse cells, whereas infection can be restored after reconstitution by ectopic expressed LDLR. Mutagenesis studies have shown that the Ligand Binding Domain (LBD) of LDLR is necessary for CCHFV infection. LBD of LDLR binds directly to CCHFV glycoprotein Gc with high affinity, supporting viral attachment and internalization into host cells. The soluble sLDLR-Fc fusion protein or anti-LDLR blocking antibody impairs infection of a variety of susceptible cells by CCHFV. In addition, gene knockout of LDLR or administration of LDLR blocking antibodies can significantly reduce viral load, pathological effects, and death following CCHFV infection in mice. Thus, pharmacological targeting of LDLR provides an effective strategy for the prevention and treatment of CCHFV infection, which is the causative agent of crimia-congo hemorrhagic fever. Accordingly, one embodiment of the present disclosure provides a method for preventing or treating a crimia-congo hemorrhagic fever virus (CCHFV) infection, or for preventing or treating a crimia-congo hemorrhagic fever in a subject, comprising administering to the subject an agent that reduces the expression or activity of LDLR, or inhibits the interaction between Low Density Lipoprotein Receptor (LDLR) and Gc glycoprotein (Gc) of CCHFV in the subject. In some embodiments, the agent is selected from the group consisting of: (a) Soluble LDLR proteins; (b) An anti-LDLR antibody or antigen-binding fragment; (c) An anti-Gc antibody or antigen-binding fragment; (d) Small molecule inhibitors of LDLR or Gc; (e) Inhibitory RNAs that inhibit LDLR expression; (f) A gene editing agent that reduces LDLR expression or activity; (g) Rapamycin; (h) A Liver X Receptor (LXR) agonist, LXR protein or a polynucleotide encoding LXR protein; (i) Retinol X Receptor (RXR) agonists, RXR proteins or polynucleotides encoding RXR proteins; (j) ZFP36 loop refers to a protein-like 1 (ZFP 36L 1) agonist, ZFP36L1 protein, or a polynucleotide encoding ZFP36L1 protein; (k) ZFP36 loop refers to a protein-like 2 (ZFP 36L 2) agonist, ZFP36L2 protein, or a polynucleotide encoding ZFP36L2 protein; (l) Progestogen and an AdipoQ receptor family member 3 (PAQR 3) agonist, a PAQR3 protein, or a polynucleotide encoding a PAQR3 protein; (m) a proprotein convertase subtilisin/kexin type 9 (PCSK 9) agonist, a PCSK9 protein, or a polynucleotide encoding a PCSK9 protein; (n) Low Density lipoproteins, and (O) an agent or molecule or combination thereof that directly or indirectly causes down-regulation of the level of LDLR or its soluble extracellular domain or CCHFV binding activity. In some embodiments, the soluble LDLR protein does n