CN108611411A - Caspr1 memebrane proteins are as the purposes prepared in neonatal meningitis drug - Google Patents
Caspr1 memebrane proteins are as the purposes prepared in neonatal meningitis drug Download PDFInfo
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Abstract
The invention belongs to targeted therapy fields, and in particular to Caspr1 memebrane proteins are as blocking Meningitic E. coil to pass through blood-brain barrier and invading the novel drugs target spot of neuron, as the purposes prepared in neonatal meningitis novel drugs.The Caspr1 memebrane proteins are as Escherichia coliE.coliThe target spot of the IbeA interactions of K1.Ligand of the present invention from intervention bacterial host（IbeA）Receptor（Caspr1）Interaction is set out, and using targeted therapy new tool, will provide new targeted drug for the prevention and treatment of Neonatal Bacterial Meningitis.
Description
Technical field
The invention belongs to targeted therapy fields, and in particular to Caspr1 memebrane proteins are passed through as blocking Meningitic E. coil
The novel drugs target spot of blood-brain barrier and invasion neuron, as the purposes prepared in neonatal meningitis novel drugs.
Background technology
Escherichia coli（Escherichia coli,E.coli) K1 plants be to cause Neonatal Bacterial Meningitis most common
Gramnegative bacterium, the incidence for the Neonatal Bacterial Meningitis being induced by it is about 1 ‰.In spite of forE.coli
The antibiotic of K1, but because bacterial resistance and most of antibiotic are difficult to the barrier structure across blood and brain tissue（Blood brain
Barrier, blood-brain barrier）Enter brain, causes case fatality rate to be up to 20 ~ 50%, survivor is often accompanied by mistake and listens, blinds, is insane
The sequelae such as epilepsy, intelligence and dyskinesia.Therefore, the control strategy for inquiring into effective Neonatal Bacterial Meningitis has important meaning
Justice.
E.coliK1 enters brain by hematogenous spread and causes meningitis.E.coliK1 causes Neonatal Bacterial Meningitis
The most important condition is to have to pass through blood-brain barrier.Therefore, if can verifyE.coliK1 passes through the mechanism of blood-brain barrier, namely obtains
E.coliThe Coupling effects for pathogen ligand-host receptor that K1 is relied on across blood-brain barrier, it will for based on ligand-
Receptor Coupling effects develop blocking outflowE.coliK1 passes through blood-brain barrier（Prevent the generation of meningitis）Drug, to realize
The prevention of meningitis.
So far,E.coliHow K1 passes through blood-brain barrier, unclear.Brain microvessel endothelial cells in vitro (brain
Microvascular endothelial cell, BMEC) be blood-brain barrier main constituents, early period of the invention, this
Inventor once cooperated to identify with foreign scholarE.coliThe virulence factor IbeA of K1 specificity（It is made of 456 amino acid）
E.coliK1 invades BMEC and plays an important role in blood-brain barrier, but its mechanism of action needs further to be studied.As can
The target protein or receptor that IbeA plays a role are searched out in people BMEC, it will be used for newborn's escherichia coli meninx to develop
Scorching protective agents provide new target drone.
People Caspr1（contactin associated protein 1, NP_003623.1）It is that a molecular weight is
The protein of 190kD is made of 1384 amino acid, is single-pass membrane protein, at first containing multiple structural domains such as lamininG
It is found to be on the axolemma for being expressed in Medullated nerve fibre ranvier's segments paranodal region, participates in the formation of myelin.
Caspr1 whether brain microvessel endothelial cells in vitro express and its with meningitis pathogenic bacteriaE.coliThe relationship of K1, mesh
It is preceding that there is not been reported both at home and abroad.
Invention content
Novel drugs target the purpose of the present invention is to provide Caspr1 memebrane proteins as prevention Neonatal Bacterial Meningitis
Point provides reliable scientific basis to prepare neonatal meningitis drug.
To achieve the goals above, the present invention adopts the following technical scheme that：
Caspr1 memebrane proteins or the structural domain of IbeA-Caspr1 interactions are as preparation newborn bacterium（E.coliK1）Property
Purposes in the drug of meningitis.
The Caspr1 memebrane proteins are as Escherichia coliE.coliThe target spot of the IbeA interactions of K1.
The structural domain of the IbeA-Caspr1 interactions is 203 to 355 amino acid peptide fragment of Caspr1 memebrane proteins and IbeA
229 to 342 amino acid peptide fragments of albumen interact.
The drug is for blocking Meningitic E. coil to pass through blood-brain barrier or blocking Meningitic E. coil invasion god
Through member.
The drug is the Treatment of Central Nervous System Diseases drug for facilitating penetration of blood-brain barrier.
The drug is oligopeptides drug or micromolecular compound drug.
The present invention discloses bacteriumE.coliThe virulence factor IbeA of K1 as ligand, host Caspr1 as receptor,
Disclosing the molecular basis that IbeA is combined with Caspr1 is：The 229-342 amino acid peptide fragment of IbeA albumen can be with Caspr1 eggs
The lamininG structural domains of the white ends N-（203-355 amino acid peptide fragments）Interaction mutually makes knots so as to IbeA- Caspr1
It screened based on structure domain, prepare the micromolecular compound medicine that can be used for Neonatal Bacterial Meningitis prevention for blocking its interaction
Object.
Another aspect of the present invention discloses the Caspr1 in experimental neonatal meningitis mouse model, BMEC for the first time
The knockout of gene significantly reducesE.coliThe incidence of newborn mice meningitis caused by K1（The knockout of Caspr1 genes is not
It is conducive toE.coliK1 passes through blood-brain barrier）, it is that target spot prepares the bacillary meninx of newborn so as to host's Caspr1 memebrane proteins
Scorching medicine.
Another aspect of the present invention, based on the Caspr1 Membrane protein conformations domain with IbeA interactions belonging to the present invention ---
The lamininG structural domains of the ends N- of Caspr1 albumen（203-355 amino acid peptide fragments）, the present inventor is in insect for intravenous injection
The Caspr1 203-355 peptide fragment recombinant proteins of cell (sf9) expression and purification, significantly reduceE.coliNew life caused by K1 is big
The meningitis incidence and the death rate of mouse block meningitis big to disclose to prepare based on Caspr1 203-355 peptide fragments
Enterobacteria passes through the oligopeptides drug of blood-brain barrier.
Another aspect of the present invention discloses for the first timeE.coliK1 can enter brain parenchym (sea after passing through blood-brain barrier
Horse), Hippocampal Neuron Cells are invaded by IbeA-Caspr1 interaction approach and cause Death of hippocampus neurons, and in insect
The Caspr1 203-355 peptide fragments recombinant proteins of cell (sf9) expression and purification have blocking effect to neuronal death；It is testing
PropertyE.coliIn K1 meningitis mouse, the rejecting of gene order corresponding with Caspr1 203-355 peptide fragments blocksE.coli
Invasion of the K1 to neuron block or inhibit so as to be prepared based on Caspr1 203-355 peptide fragmentsE.coliK1 is invaded
The drug of neuron.
Another aspect of the present invention, the present invention belonging to Caspr1 be only expressed in brain microvessel endothelial cells in vitro rather than body
Other position vascular endothelial cells and IbeA albumen by its 229-342 amino acid peptide fragment and Caspr1 interaction features, to
Can be based on IbeA 4 protein 22 9-342 amino acid peptide fragments, the central nervous system disease that preparation facilitates penetration of blood-brain barrier is controlled
Treat drug.
Compared with the prior art, the advantages of the present invention are as follows：
The prior art there is no effective method for Neonatal Bacterial Meningitis is prevented, newborn suffer from meningitis it
After mostly use broad-spectrum antibiotic therapy, bacterium is susceptible to drug resistance.Ligand of the present invention from intervention bacterium-host（IbeA）-
Receptor（Caspr1）Interaction is set out, and using targeted therapy new tool, for the prevention of Neonatal Bacterial Meningitis and will be controlled
It treats and new targeted drug is provided.
Description of the drawings
Fig. 1 shows that Caspr1 is expressed in the cell membrane of brain microvessel endothelial cells in vitro（A, with VE-cadherin common locations）And mouse
The lumen of vessels side cell membrane of brain microvessel endothelial cells in vitro（B, Lumen）.
Fig. 2 shows that Caspr1 is only expressed in brain microvessel endothelial cells in vitro rather than body other position vascular endothelial cells
(CD31 is vessel landmarks object).
Fig. 3 shows that IbeA and Caspr1 exists and interacts.A:Caspr1 cDNA recombinant plasmid quilts with His labels
It is transfected into HEK293 cells, cell pyrolysis liquid and the IbeA for carrying GST labels（GST-IbeA）It is incubated, through GST pull-down
Product be Western blot（His antibody）；B：After the people BMEC of in vitro culture is cleaved, cell pyrolysis liquid with carry GST
The IbeA of label is incubated, and GST pull-down products are through Western blot (Caspr1 antibody）Analysis.
Fig. 4 shows that the molecular basis that is combined with Caspr1 of IbeA is that the 229-342 amino acid peptide fragment of IbeA albumen can be with
The lamininG structural domains of the ends N- of Caspr1 albumen（203-355 amino acid peptide fragments）In conjunction with.A：Show Caspr1 structural domains and
Truncated Caspr1 cloned sequences；B：The truncated ends C- carry multiple Caspr1 cDNA recombinant plasmids of His labels, through body
After outer transcription/translation, product done after being incubated altogether with GST-IbeA respectively GST pull-down, pull-down products by with
Make Western blot analyses（His antibody）；C：Multiple Caspr1 cDNAs of the truncated ends C- with His labels recombinate matter
Grain is transfected HEK293T cells, and cell pyrolysis liquid is incubated with GST-IbeA, and GST pull-down products are used as Western
Blot is analyzed（His antibody）；D：Caspr1 203-355 and Caspr1 356-538 cDNA recombinant plasmids with His labels
After in-vitro transcription/translation, product does GST pull-down, pull-down products after being incubated altogether with GST-IbeA respectively
It is used as Western blot analyses（His antibody）；E：Show the overall length of IbeA and truncated IbeA cloned sequences；F：Through turning in vitro
The Caspr1 203-355 peptide fragments with His labels of record/translation are recombinated with multiple truncation IbeA with GST labels respectively
Albumen is incubated, and GST pull-down products are used as Western blot analyses（His antibody）.
Fig. 5 shows that the knockout of Caspr1 genes in mouse BMEC significantly reducesE.coliNewborn mice brain caused by K1
The incidence of film inflammation.A：Caspr1 conditional gene knockouts mouse building process in BMEC； B：Caspr1 conditionitys base in BMEC
Because of the identification of knock-out mice（CD31 label vasculars）；C：It is shown in the mouse of Caspr1 gene knockouts in BMEC,E.coli K1
The incidence of newborn rat meningitis is caused to significantly reduce；D：The HE of brain tissue slice is dyed, displayE.coliIt is wild after K1 infection
The difference of raw type mouse and Caspr1 conditional gene knockout mouse brain film thickness and inflammatory cell infiltration.
Fig. 6 display intravenous injection the present inventor is in the Caspr1 203-355 peptide fragment weights of insect cell (sf9) expression and purification
Histone significantly reducesE.coliThe meningitis incidence and the death rate of neonate rat caused by K1.A：Show thin through insect
Born of the same parents（Sf9) the GST-Caspr1 203-355 recombinant proteins of expression and purification can very well be combined with IbeA albumen；B：Show GST-
The degradation situation of Caspr1 203-355 recombinant proteins in blood；C：Show that GST-Caspr1 203-355 recombinant proteins are notable
ReduceE.coliThe meningitis incidence of neonate rat caused by K1；D：Show GST-Caspr1 203-355 recombinant proteins pair
The blocking effect of meninx inflammatory reaction（Meninx thickness and neutrophil infiltration are in significant difference）；E：Show GST-Caspr1
203-355 recombinant proteins significantly extend the survival rate for the neonate rat for suffering from meningitis.
Fig. 7 shows the present inventor in the Caspr1 203-355 peptide fragment recombinant proteins pair of insect cell (sf9) expression and purificationE.coliK1, which invades neuronal death, has blocking effect（A）；The Caspr1 203-355 peptide fragments built from inventor are removed
Transgenic mice in isolate neuron（B, heterozygote）, the results show that gene corresponding with Caspr1 203-355 peptide fragments
The rejecting of sequence blocksE.coliInvasion of the K1 to neuron.
Fig. 8 is host Caspr1E.coliK1 passes through blood-brain barrier to cause the receptor of meningitis and prevents the figure of target spot
Solution：It infects into bloodE.coliK1 discharges its virulence factor IbeA, IbeA and is located at after being contacted with brain microvessel endothelial cells in vitro
Brain microvessel endothelial cells in vitro lumen of vessels side memebrane protein Caspr1 is combined, and then the FAK- Rac1 signal paths in activating cell,
CauseE.coliK1 invades brain microvessel endothelial cells in vitro and causes meningitis and neuronal death across blood-brain barrier
(E.coliK1 is invaded by Caspr1 caused by neuron).
Specific implementation mode
The present inventor passes through in-depth study, discloses Caspr1 memebrane proteins or IbeA-Caspr1 interactions for the first time in meningitis
Escherichia coli pass through blood-brain barrier, invasion neuron（Lead to meningitis）In effect.To IbeA-Caspr1 film eggs
White interaction structural domain or Caspr1 memebrane proteins can be used as drug target exploitation prevention Neonatal Bacterial Meningitis occurrence and development
Drug.
The discovery of 1. IbeA interactions albumen (Caspr1) of embodiment.
The discovery of the present inventor's early-stage study is worked asE.coliAfter K1 is contacted with BMEC, IbeA can be byE.coliK1 is secreted into
Outside bacterial cell, therefore the present inventor using IbeA gene clonings to pGBK and is transformed into yeast strain Y187 as bait, the bacterium
Strain and the cDNA clone libraries of BMEC containing someone（CDNA clone is to pGAD）AH109 plants of hybridization/mating of yeast, pass through this ferment
The screening of female two-hybrid techniques and positive colony sequencing obtain the Caspr1 with IbeA interactions.Subsequent experimental identify IbeA with
The interaction of Caspr1：First, the Caspr1 recombinant expression plasmids with His-tag labels are transfected HEK293T cells, cell
Lysate is incubated with the IbeA with GST labels, and GST pull-down products are through Western blot (His antibody）Analysis card
Real IbeA and Caspr1 interactions（Fig. 3 A）；Second is that after the people BMEC of in vitro culture is cleaved, cell pyrolysis liquid is marked with GST
The IbeA of label is incubated, and GST pull-down products are through Western blot (Caspr1 antibody）Analysis confirms IbeA and Caspr1
Interaction（Fig. 3 B）.To disclose host cell（BMEC）In Caspr1 beE.coliThe target practice egg of K1 virulence factors IbeA
In vain.
2. Caspr1 of embodiment is expressed in the identification of the cell membrane of BMEC lumen of vessels side.
Disclose the expression for having Caspr1 in BMEC for the first time in view of the present inventor, therefore whether top priority is to determine Caspr1
It is expressed in the cell membrane whether BMEC cell membranes, Caspr1 are expressed in BMEC lumen of vessels side（Only in lumen of vessels side, IbeA
Just it is convenient in combination）, Caspr1 whether be only expressed in blood vessel of the cerebral microvascular without being expressed in other positions of body（Only table
Up in BMEC, capable of just showing the thermophilic brain of Meningitic E. coil specificity）.Vitro in primary has been separately cultured patient with operation abandonment
The brain microvessel endothelial cells in vitro of brain tissue（HBMEC ratifies by school Ethics Committee）, after paraformaldehyde is fixed, with for people
Caspr1 specific antibodies carry out immunostaining, and fluorescence microscope arrives：Caspr1 is expressed in people's BMEC cell membranes（Figure 1A）；
Immuno-electron microscope from Mice brain tissues slice shows that Caspr1 is expressed in the cell membrane of BMEC lumen of vessels side（Figure 1B）；And
Different tissues of mice prepares frozen section after OCT is embedded, and the mark molecule CD31 antibody of Caspr1 antibody and blood vessel dyes altogether,
Immunofluorescence results show that Caspr1 is only expressed in BMEC, and the expression of Caspr1 is not detected in the blood vessel organized outside brain（Figure
2）.To discloseE.coliThe IbeA of K1 secretions and the reasonability that Caspr1 is combined on host BMEC.
The identification of 3. IbeA- Caspr1 interaction structural domains of embodiment.
According to Caspr1 extracellular domains (Fig. 4 A), the present inventor constructs the truncated ends C- successively and carries His first
Multiple Caspr1 cDNA recombinant plasmids of label, after in-vitro transcription/translation, after product is incubated with GST-IbeA altogether respectively
GST pull-down are, pull-down products are used as Western blot analyses（His antibody）, as a result it is shown in
In all structural domains of Caspr1, only 203 to 538 peptide fragments（Including two structural domains of LamG1 and LamG2）It can be with IbeA interactions
（Fig. 4 B）；Further multiple Caspr1 cDNA recombinant plasmids of the truncated ends C- with His labels are transfected
HEK293T cells, cell pyrolysis liquid are incubated with GST-IbeA, and GST pull-down products are used as Western blot analyses
（His antibody）, result also turns out that the 203-538 peptide fragments of only Caspr1 can be with IbeA interactions（Fig. 4 C）；Further to find
The minimum peptide fragment structural domain combined with IbeA in Caspr1, the present inventor is by the Caspr1 203-355 with His labels（It is corresponding
LamG1）With Caspr1 356-538（Corresponding LamG2）After cDNA recombinant plasmids carry out in-vitro transcription/translation, product difference
GST pull-down, pull-down products are done after being incubated altogether with GST-IbeA is used as Western blot analyses（His is anti-
Body）, as a result display only Caspr1 203-355（The LamG1 of the ends N-）Peptide fragment can be combined with IbeA（Fig. 4 D）.To find
In IbeA with Caspr1 203-355（LamG1 structural domains）The minimum peptide fragment of interaction, the present inventor construct with GST labels
The overall length of IbeA and Bu Tong truncated IbeA cloned sequences（Fig. 4 E）, inverted bacterium BL21（DE3）Expression and purification obtains difference
The GST-IbeA recombinant proteins of size, these recombinant proteins respectively at through in-vitro transcription/translation with His labels
Caspr1 203-355 peptide fragments are incubated, and GST pull-down products are used as Western blot analyses（His antibody）, knot
Fruit shows that the 229-342 amino acid peptide fragment of IbeA albumen can be with the LamG1 structural domains of the ends N- of Caspr1 albumen（203-
355 amino acid peptide fragments）In conjunction with（Fig. 4 F）.It can be screened based on IbeA-Caspr1 interaction structural domains to disclose, prepare resistance
The micromolecular compound drug that can be used for Neonatal Bacterial Meningitis prevention for its interaction of breaking.
4. Meningitic E. coil of embodiment passes through the Caspr1 that blood-brain barrier needs BMEC to express.
The experiment in vitro of the present inventor proves that RNAi the or Caspr1 203-355 peptide fragments of Caspr1 deletes in people BMEC
Except causingE.coliK1 internalizations are substantially reduced to the quantity in BMEC.To obtain internal evidence, the present inventor constructs for the first time
Caspr1 conditional gene knockouts mouse in BMEC（Fig. 5 A, B）：The present inventor is using homologous recombination technique in mouseCaspr1The
2,3 exon both sides add the sites Loxp, obtainCaspr1 Loxp/LoxpTransgenic mice, then with brain microvessel endothelial cells in vitro
Specific expressed Cre recombinases（The Cre expression of VE-cadherin-Cre, VE-cadherin promoter regulation）Mouse mating breeding
It obtainsCaspr1 loxP/+ ; VE-cadherin Cre/+ Hybrid mice, hybrid mice selfing obtain in BMECCaspr1It knocks out
Mouse.It is carried out using the mouseE.coliAs a result K1 infection experiments are shown in the small of Caspr1 gene knockouts in BMEC
Mouse,E.coliK1 causes the incidence of newborn rat meningitis to significantly reduce（Fig. 5 C）；The HE dyeing of Mice brain tissues slice is aobvious
Show,E.coliThere are significance differences for the meningitis degree of wild-type mice and Caspr1 conditional gene knockout mouse after K1 infection
It is different：In Caspr1 conditional gene knockout mouse, meninx thickness and inflammatory cell infiltration substantially reduce（Fig. 5 D）.To disclose
Neonatal Bacterial Meningitis medicine can be prepared by target spot of host Caspr1 memebrane proteins.
Embodiment 5.E.coliK1 invasion neurons are also required to rely on the interaction of IbeA- Caspr1.
The inventors discovered that across blood-brain barrierE.coliK1 can invade hippocampal neuron（Lead to Neuron Apoptosis）,
The process is also required to rely on the presence of Caspr1.It is small that the present inventor constructs the transgenosis that Caspr1 203-355 peptide fragments are removed
Mouse, the mouse are difficult to obtain homozygote, we have been separately cultured after the birth that Caspr1 203-355 peptide fragments are removed 3 days miscellaneous
Zygote mouse hippocampal neuron（Fig. 7 B, heterozygote）, bacteria attack experiment display, base corresponding with Caspr1 203-355 peptide fragments
Because the rejecting of sequence is blocked or is inhibitedE.coliInvasion of the K1 to neuron；The present inventor expresses pure in insect cell (sf9)
The Caspr1 203-355 peptide fragment recombinant proteins pair of changeE.coliK1, which invades neuronal death, has significant blocking effect（Figure
7A）.It can be prepared based on Caspr1 203-355 peptide fragments and block or inhibit to discloseE.coliK1 invades neuron
Drug.
Use of the 6. Caspr1 203-355 peptide fragments recombinant proteins of embodiment in the prevention of experimental neonatal rat brain membrane inflammation
On the way.
The present inventor is in insect cell (sf9) expression and purification Caspr1 203- that can be very well combined with IbeA albumen
355 peptide fragment recombinant proteins（Fig. 6 A）, according to palliating degradation degree of the Caspr1 203-355 peptide fragment recombinant proteins in rat blood
Detection（Fig. 6 B）, application of the Caspr1 203-355 peptide fragments recombinant proteins in experimental neonatal rat brain membrane inflammation is devised, is tied
Fruit shows：The present inventor is injected intravenously in the Caspr1 203-355 peptide fragment recombinant proteins of insect cell (sf9) expression and purification,
It significantly reducesE.coliThe meningitis incidence of neonate rat caused by K1（As shown in table 1 below）：
The HE coloration results of brain tissue slice, GST-Caspr1 203-355 recombinant proteins show anti-to the scorching disease of rat brain membrane
The blocking effect answered（Fig. 6 D）；GST-Caspr1 203-355 recombinant proteins significantly extend the life for the neonate rat for suffering from meningitis
Deposit rate（Fig. 6 E）.Meningitic E. coil is blocked to pass through blood to disclose to prepare based on Caspr1 203-355 peptide fragments
The oligopeptides drug of brain barrier.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, any made by repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (7)
1.Caspr1 memebrane proteins or the structural domain of IbeA-Caspr1 interactions are as the medicine for preparing Neonatal Bacterial Meningitis
Purposes in object.
2. Caspr1 memebrane proteins according to claim 1 or the structural domain of IbeA-Caspr1 interactions are new as preparing
Purposes in the drug of raw youngster's meningitis, which is characterized in that the meningitis is drawn for K1 plants by Escherichia coli
It rises.
3. Caspr1 memebrane proteins according to claim 1 or the structural domain of IbeA-Caspr1 interactions are new as preparing
Purposes in the drug of raw youngster's meningitis, which is characterized in that the Caspr1 memebrane proteins are as Escherichia coliE.coliThe target spot of the IbeA interactions of K1.
4. Caspr1 memebrane proteins according to claim 1 or the structural domain of IbeA-Caspr1 interactions are new as preparing
Purposes in the drug of raw youngster's meningitis, which is characterized in that the structural domain of the IbeA-Caspr1 interactions is
203 to 355 amino acid peptide fragment of Caspr1 memebrane proteins and 229 to 342 amino acid peptide fragments of IbeA albumen interact.
5. Caspr1 memebrane proteins according to claim 1 or the structural domain of IbeA-Caspr1 interactions are new as preparing
Purposes in the drug of raw youngster's meningitis, which is characterized in that the drug is for blocking Meningitic E. coil to pass through
Blood-brain barrier blocks Meningitic E. coil to invade neuron.
6. Caspr1 memebrane proteins according to claim 1 or the structural domain of IbeA-Caspr1 interactions are new as preparing
Purposes in the drug of raw youngster's meningitis, which is characterized in that the drug is the maincenter god for facilitating penetration of blood-brain barrier
Through systemic disease medicine.
7. Caspr1 memebrane proteins according to claim 1 or the structural domain of IbeA-Caspr1 interactions are new as preparing
Purposes in the drug of raw youngster's meningitis, which is characterized in that the drug is oligopeptides drug or micromolecular compound medicine
Object.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110787168A (en) * | 2019-11-06 | 2020-02-14 | 中国医科大学 | Small molecule compound C29H28Cl2N6Application of O in E.coli meningitis |
| CN110787168B (en) * | 2019-11-06 | 2022-06-24 | 中国医科大学 | Small molecule compound C29H28Cl2N6Application of O in E.coli meningitis |
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