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CN-122028921-A - Use of TMED10 as target in the treatment of inflammation

CN122028921ACN 122028921 ACN122028921 ACN 122028921ACN-122028921-A

Abstract

Use of an E-TMED10 inhibitor for the preparation of a product for the treatment and/or prophylaxis of inflammation. The interaction of the E protein of coronavirus with TMED10 (E-TMED 10) is a potential molecular mechanism driving coronavirus-induced excessive inflammation and is also a potential therapeutic target against the deleterious effects of coronavirus-induced inflammation. Blocking or reducing interaction of coronavirus E protein and TMED10 can realize the effect of reducing release of proinflammatory factors and reducing lung inflammation.

Inventors

  • ZHANG MIN
  • GE LIANG
  • LIU LEI
  • ZHANG LIJINGYAO
  • HAO XINYAN
  • TIAN BOXUE

Assignees

  • 清华大学

Dates

Publication Date
20260512
Application Date
20240207

Claims (20)

  1. Use of an E-TMED10 inhibitor for the preparation of a product for the treatment and/or prophylaxis of inflammation, wherein E-TMED10 is the interaction of coronavirus E protein with TMED10, and wherein the E-TMED10 inhibitor blocks or reduces the interaction of coronavirus E protein with TMED10, said inflammation being an inflammation caused by a coronavirus infection.
  2. The use according to claim 1, wherein the E-TMED10 inhibitor treats and/or prevents inflammation by blocking or reducing oligomerization of TMED 10.
  3. The use according to claim 1 or 2, wherein the E-TMED10 inhibitor treats and/or prevents inflammation by blocking or reducing UcPS (non-classical secretion) cargo transport to ERGIC.
  4. The use according to any one of claims 1 to 3, wherein the E-TMED10 inhibitor is used to block or reduce the transport of inflammatory factors to vesicles in the UcPS pathway.
  5. The use according to any one of claims 1 to 3, wherein the E-TMED10 inhibitor blocks or reduces translocation of inflammatory factors into the membrane.
  6. The use according to any one of claims 1 to 3, wherein the E-TMED10 inhibitor treats and/or prevents inflammation by blocking or reducing the release of inflammatory factors in the UcPS pathway.
  7. The use according to claim 4 or 5, wherein the inflammatory factor comprises an inflammatory factor of the IL1 family, such as one or more of IL1 β, IL33, IL36 α, IL1 α or IL 18.
  8. The use according to claim 1, wherein the E-TMED10 inhibitor targets the cytoplasmic C-terminus of TMED10, preferably a sequence comprising YLRRFFKAKKLIE (SEQ ID NO: 2).
  9. The use according to claim 1, wherein the E-TMED10 inhibitor targets the SS motif or the DS motif of the coronavirus E protein, wherein S represents serine and D represents aspartic acid.
  10. The use according to claim 1, wherein the inflammation comprises pneumonia, nephritis, hepatitis or splenitis.
  11. The use according to claim 1, wherein the inflammation comprises lung injury caused by infiltration of immune cells.
  12. The use according to claim 1, wherein said coronavirus infects vertebrates such as humans, mice, pigs, cats, dogs, wolves, cows or birds, wherein said birds comprise poultry or birds.
  13. The use according to claim 1, wherein said coronavirus comprises the genus α, β, γ or δ, preferably β.
  14. The use according to claim 13, wherein said alpha coronavirus comprises one or more of human coronavirus 229E or a mutant thereof, human coronavirus NL63 or a mutant thereof, human coronavirus HKU1 or a mutant thereof, human hepialus coronavirus HKU8 or a mutant thereof, chrysanthemumps coronavirus HKU2 or a mutant thereof, porcine epidemic diarrhea virus (Porcine EPIDEMIC DIARRHEA virus, PEDV) or a mutant thereof, porcine transmissible gastroenteritis virus (Transmissible gastroenteritis virus, TGEV) or a mutant thereof, canine coronavirus (Canine coronavirus, CCoV) or a mutant thereof, or feline coronavirus (Feline coronavirus, FCoV) or a mutant thereof.
  15. The use according to claim 13, wherein said β -genus coronavirus comprises one or more of human coronavirus HKU1 or a mutant thereof, murine coronavirus or a mutant thereof, bata coronavirus HKU5 or a mutant thereof, bata coronavirus HKU9 or a mutant thereof, severe acute respiratory syndrome (severe acute respiratory syndromes, SARS) or a mutant thereof, MERS or a mutant thereof, SARS-CoV-2 or a mutant thereof, bovine coronavirus (Bovine coronavirus, BCoV) or a mutant thereof, human coronavirus OC43 or a mutant thereof, equine coronavirus (Equlne coronavirus, ECoV) or a mutant thereof, porcine hemagglutinating encephalomyelitis virus (Porcine hemagglutinating encephalomyelitis, PHEV) or a mutant thereof, canine respiratory tract coronavirus (Canine respiratory coronavirus, crCoV) or a mutant thereof; Preferably, the murine coronavirus comprises one or more of a murine hepatitis virus (Mouse hepatitis virus, MHV), a rat coronavirus or a guano-seabird virus; Preferably, the SARS mutant comprises one or more of BJ01, urbani, torr 2, CUHK or HKV; Preferably, the SARS-CoV-2 mutant is selected from Alpha, beta, gamma, delta, lambda or Omiron.
  16. Use according to claim 13, wherein said gamma coronavirus comprises an avian coronavirus such as avian infectious bronchitis virus (Infectious bronchitis virus, IBV) or a mutant thereof, a beluga coronavirus SW1 (Beluga whale coronavirus SW1, BWCoV-SW 1) or a mutant thereof; preferably, avian coronaviruses include coronaviruses that cause infection of birds such as chickens, turkeys, sparks, ducks, geese, pigeons.
  17. The use according to claim 13, wherein the delta coronavirus comprises one or more of a night warrior coronavirus (Bulbul coronavirus HKU, buCoV HKU 11) or a mutant thereof, a thrush coronavirus (Thrush coronavirus HKU, thCoV HKU 12) or a mutant thereof, a vinous coronavirus (Thrush coronavirus HKU, thCoV HKU) or a mutant thereof, asian leopard cat coronavirus (Asian Leopard Cats Coronavirus, ALCCoV) or a mutant thereof, chinese ferret coronavirus (CHINESE FERRET-badger Coronavirus, CFBCoV) or a mutant thereof, a porcine delta coronavirus (Por-cine Delatcoronavirus, PDCoV) or a mutant thereof, a sparrow coronavirus (White-eye Coronavirus, WECoV) or a mutant thereof, a sparrow coronavirus (Sparrow Coronavirus, SPCoV) or a mutant thereof, a magpie robin coronavirus (Magpie robin Coronavirus, MRCoV) or a mutant thereof, a night heron coronavirus (Night heron Coronavirus, NHCoV) or a mutant thereof, a wild duck coronavirus (Wigeon Coronavirus, wiCoV) or a mutant thereof, a black water coronavirus (Common Moorhen Coronavirus, CMCoV) or a mutant thereof.
  18. The use according to any one of claims 1 to 17, wherein the coronavirus comprises an SS motif or a DS motif for its E protein, wherein S represents serine and D represents aspartic acid.
  19. The use of claim 1, wherein the E-TMED10 inhibitor comprises a small molecule, a traditional Chinese medicine extract, an antibody, RNAi, an agent that knocks out TMED10, or a cytotherapeutic agent.
  20. The use according to claim 19, wherein the E-TMED10 inhibitor comprises an agent that expresses or overexpresses the cytoplasmic domain of the coronavirus E protein, such as a vector that expresses or overexpresses the cytoplasmic domain of the coronavirus E protein; Preferably, the vector may be a viral vector or a non-viral vector.

Description

Use of TMED10 as target in the treatment of inflammation Technical Field The invention relates to the technical field of biological medicine, in particular to an application of TMED10 serving as a target spot in treating inflammation, and especially relates to an application of an E-TMED10 inhibitor in treating and/or preventing inflammation. Background The transmembrane emp24 domain-containing protein (TMED) family is generalized in humans into the alpha (TMED 4, 9), beta (TMED 2), gamma (TMED 1,3,5,6, 7) and delta (TMED 10) 4 subfamilies, 9 members of which are important mediators of intracellular protein transport, involved in normal embryonic development and the pathogenic processes of many human diseases. Prior art document ：TMED family genes and their roles in human diseases(Lv Zhou,International Journal of Medical Sciences,2023) reviews the relationships between members of the TMED families and human diseases, including tumors, diabetes, neurodegenerative diseases, non-alcoholic fatty liver disease, dilated cardiomyopathy, mucin 1 nephropathy, and sjogren's syndrome, among others. For the relationship between TMED10 and inflammation, the prior art document A Translocation Pathway for Vesicle-Mediated Unconventional Protein Secretion (Min Zhang, cell, 2020) discloses that TMED10 directly mediates membrane translocation of cytoplasmic proteins lacking signal peptides into liposomes, i.e., TMED10 promotes secretion of inflammatory factors by mediating a non-classical secretory pathway. It is well known that excessive and uncontrolled release of pro-inflammatory factors in large amounts during pathogen infections such as coronaviruses (e.g., SARS2, SARS and MERS) can trigger immune pathogenesis leading to extensive tissue damage throughout the human body, including acute lung injury. This process is associated with the occurrence of multiple organ dysfunction syndrome and an increased risk of mortality. The rise in circulating inflammatory factors including interleukin-1 (IL 1), interleukin-6 (IL 6), interleukin-12 (IL 12), interferon-gamma (ifnγ) and tumor necrosis factor-alpha (TNF- α) in the bloodstream of patients infected with coronaviruses has a great deal of relevance to the severity of the disease. However, the precise cellular mechanisms by which coronaviruses regulate the host inflammatory response, particularly in terms of pro-inflammatory factor release, remain largely unresolved. Disclosure of Invention To address the deficiencies of the prior art, the present application discloses a molecular mechanism that drives coronavirus-induced excessive inflammation. That is, the envelope protein (E protein) of coronaviruses, but not other proteins of viruses, enhances pulmonary inflammation by activating the TMED 10-mediated UcPS pathway in which the IL1 family is released. Specifically, interaction of the coronavirus E protein with TMED10 enhances oligomerization of TMED10, facilitates UcPS cargo transport to ERGIC, and mechanistically, the E protein of severe coronavirus has an SS/SD motif that facilitates interaction with TMED10, thereby facilitating oligomerization, a translocation process necessary for secretion of various inflammatory factors through UcPS. In addition, the application further verifies that blocking or reducing the interaction of E protein with TMED10 can reduce the release of pro-inflammatory factors and reduce pulmonary inflammation. The invention provides the use of an E-TMED10 inhibitor for the preparation of a product for the treatment and/or prophylaxis of inflammation. E-TMED10 is the interaction of the coronavirus E protein (envelope protein) with TMED 10. Preferably the interaction of protein E with TMED10 during the formation of the complex. E-TMED10 inhibitors block or reduce the interaction of coronavirus E protein with TMED 10. Preferably, the E-TMED10 inhibitor treats and/or prevents inflammation by blocking or reducing oligomerization of TMED 10. Preferably, the E-TMED10 inhibitor treats and/or prevents inflammation by blocking or reducing UcPS cargo transport to ERGIC. Preferably, the E-TMED10 inhibitor blocks or reduces the transport of inflammatory factors to vesicles in the UcPS pathway. Preferably, the E-TMED10 inhibitor blocks or reduces translocation of inflammatory factors into the membrane. Preferably, the E-TMED10 inhibitor treats and/or prevents inflammation by blocking or reducing inflammatory factor release in the UcPS pathway. Preferably, the inflammatory factor comprises an inflammatory factor of the IL1 family, such as one or more of IL1 β (preferably mll 1 β), IL33 (preferably mll 33), IL36 α (preferably mll 36 α), IL1 α (preferably mll 1 α) or IL18 (preferably mll 18). Preferably, the E-TMED10 inhibitor targets the endoluminal domain GOLD, endoluminal domain CC, transmembrane domain (TM) or cytoplasmic C-terminus (CT), further preferably targets the cytoplasmic C-terminus of TMED10, preferably targets a sequence comprising YLRRFFKAKKLIE (SEQ ID